TWI621619B - Ethynyl derivatives - Google Patents
Ethynyl derivatives Download PDFInfo
- Publication number
- TWI621619B TWI621619B TW105124484A TW105124484A TWI621619B TW I621619 B TWI621619 B TW I621619B TW 105124484 A TW105124484 A TW 105124484A TW 105124484 A TW105124484 A TW 105124484A TW I621619 B TWI621619 B TW I621619B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- phenyl
- pyrimidine
- trione
- phenylethynyl
- Prior art date
Links
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 12
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 10
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 10
- 230000003287 optical effect Effects 0.000 claims abstract description 10
- 230000036506 anxiety Effects 0.000 claims abstract description 9
- 206010003805 Autism Diseases 0.000 claims abstract description 7
- 208000020706 Autistic disease Diseases 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims abstract description 7
- 206010047700 Vomiting Diseases 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 7
- 230000008673 vomiting Effects 0.000 claims abstract description 7
- 230000004112 neuroprotection Effects 0.000 claims abstract description 6
- -1 = O Chemical group 0.000 claims description 127
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 96
- 229910052799 carbon Inorganic materials 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- GNJWLMMWHACAHX-LJAQVGFWSA-N (9aS)-2-(2-cyclopropyloxypyrimidin-5-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C1(CC1)OC1=NC=C(C=N1)N1C([C@]2(N(C(N(C(C2)=O)C2=C(C=C(C=C2F)C#CC2=CC=CC=C2)F)=O)CC1)C)=O GNJWLMMWHACAHX-LJAQVGFWSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 15
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 12
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 11
- VUVIDSLUFICAJJ-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=CN=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 VUVIDSLUFICAJJ-MHZLTWQESA-N 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- OTZKOOYRTIWVNF-MHZLTWQESA-N (9aS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=NC=C1)C2=O)C1=C(Cl)C=C(C=C1F)C#CC1=CC=CC=C1 OTZKOOYRTIWVNF-MHZLTWQESA-N 0.000 claims description 7
- BGUAXCZYNNTIGR-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CN=CC=N1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 BGUAXCZYNNTIGR-SANMLTNESA-N 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- BGUAXCZYNNTIGR-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC=CN=C1)=O)C)=O BGUAXCZYNNTIGR-UHFFFAOYSA-N 0.000 claims description 5
- VUVIDSLUFICAJJ-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC=CC=1)=O)C)=O VUVIDSLUFICAJJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- ZWPLPWADHRVHHH-MUUNZHRXSA-N (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COC[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=CN=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 ZWPLPWADHRVHHH-MUUNZHRXSA-N 0.000 claims description 4
- ZWPLPWADHRVHHH-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC=CC=1)=O)COC)=O ZWPLPWADHRVHHH-UHFFFAOYSA-N 0.000 claims description 4
- VNWNCKYBIZUVAX-UHFFFAOYSA-N 7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound ClC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC=CC=1)=O)C)=O VNWNCKYBIZUVAX-UHFFFAOYSA-N 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- RVOYDRUSMXEXNZ-MHZLTWQESA-N (9aS)-2-(2-chloropyridin-4-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC(Cl)=NC=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 RVOYDRUSMXEXNZ-MHZLTWQESA-N 0.000 claims description 3
- AVFVNHLHJYTUFF-MHZLTWQESA-N (9aS)-2-(6-chloropyridin-3-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=C(Cl)N=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 AVFVNHLHJYTUFF-MHZLTWQESA-N 0.000 claims description 3
- JAKSTUGBJWGFCB-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(1-ethylpyrazol-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CCN1C=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 JAKSTUGBJWGFCB-MHZLTWQESA-N 0.000 claims description 3
- WVCNOLGBRUPCLT-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-ethoxypyrimidin-5-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CCOC1=NC=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 WVCNOLGBRUPCLT-NDEPHWFRSA-N 0.000 claims description 3
- RWKFZDCJUKSRRN-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-imidazol-1-ylethyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(CCN1C=CN=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 RWKFZDCJUKSRRN-MHZLTWQESA-N 0.000 claims description 3
- UKRATCLUPBWUPA-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-methoxypyrimidin-5-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COC1=NC=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 UKRATCLUPBWUPA-MHZLTWQESA-N 0.000 claims description 3
- TWMURVIWINXURA-LJAQVGFWSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(3,5-dimethylpyridin-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC1=CN=CC(C)=C1N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 TWMURVIWINXURA-LJAQVGFWSA-N 0.000 claims description 3
- FZSXHTPPCUENBZ-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(6-methoxypyridin-3-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COC1=CC=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 FZSXHTPPCUENBZ-NDEPHWFRSA-N 0.000 claims description 3
- JILJIRCYONPHSF-LJAQVGFWSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(2-fluorophenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(CC1=C(F)C=CC=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 JILJIRCYONPHSF-LJAQVGFWSA-N 0.000 claims description 3
- JCTOSCLGJVEJLD-LJAQVGFWSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(3-fluorophenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(CC1=CC(F)=CC=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 JCTOSCLGJVEJLD-LJAQVGFWSA-N 0.000 claims description 3
- OIZDWNLRUVLGQE-LJAQVGFWSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[1-(3-methoxypropyl)pyrazol-4-yl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COCCCN1C=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 OIZDWNLRUVLGQE-LJAQVGFWSA-N 0.000 claims description 3
- GRZYHQFBZWHKAR-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=CN=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 GRZYHQFBZWHKAR-NDEPHWFRSA-N 0.000 claims description 3
- OOYXOQCKADAHQT-VWLOTQADSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methyl-1,2,4-triazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1C=NC(=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 OOYXOQCKADAHQT-VWLOTQADSA-N 0.000 claims description 3
- OZUGEOGFDBSBPW-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1C=CC(=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 OZUGEOGFDBSBPW-SANMLTNESA-N 0.000 claims description 3
- QPMZDQLPIGCTRA-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1C=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 QPMZDQLPIGCTRA-SANMLTNESA-N 0.000 claims description 3
- DJLAFUAJZADFTG-QHCPKHFHSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2,2,2-trifluoroethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(CC(F)(F)F)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 DJLAFUAJZADFTG-QHCPKHFHSA-N 0.000 claims description 3
- XMXJHRSYTJPWIV-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1N=CC=C1N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 XMXJHRSYTJPWIV-SANMLTNESA-N 0.000 claims description 3
- JJRRVVPPKJFBLS-XIFFEERXSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-phenylmethoxypyrimidin-5-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CN=C(OCC3=CC=CC=C3)N=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 JJRRVVPPKJFBLS-XIFFEERXSA-N 0.000 claims description 3
- OPEYJKNEIWCKSP-LJAQVGFWSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-propan-2-yloxypyrimidin-5-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC(C)OC1=NC=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 OPEYJKNEIWCKSP-LJAQVGFWSA-N 0.000 claims description 3
- LFVRFNNIJUERRC-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC1=C(N=CN=C1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 LFVRFNNIJUERRC-MHZLTWQESA-N 0.000 claims description 3
- UJFCEGZDJCUBRY-XIFFEERXSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-phenylmethoxypyrazin-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C2=O)C1=CN=C(OCC2=CC=CC=C2)C=N1)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 UJFCEGZDJCUBRY-XIFFEERXSA-N 0.000 claims description 3
- AYKDOFVOHNSCDY-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC1=NC=NC(=C1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 AYKDOFVOHNSCDY-MHZLTWQESA-N 0.000 claims description 3
- OWQBNCXISVCDMJ-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-(1-methylpyrazol-4-yl)ethyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1C=C(CCN2CCN3C(=O)N(C(=O)C[C@@]3(C)C2=O)C2=C(F)C=C(C=C2F)C#CC2=CC=CC=C2)C=N1 OWQBNCXISVCDMJ-NDEPHWFRSA-N 0.000 claims description 3
- DHQUZMFOKQIWHZ-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-(2-methylpyrazol-3-yl)ethyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1N=CC=C1CCN1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 DHQUZMFOKQIWHZ-NDEPHWFRSA-N 0.000 claims description 3
- HSTARMKMXDEIBC-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=NC=CC=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 HSTARMKMXDEIBC-MHZLTWQESA-N 0.000 claims description 3
- JNNRNTKYQGBPDC-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=NC=N1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=C(F)C=CC=C1 JNNRNTKYQGBPDC-SANMLTNESA-N 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- PNAFRZGWUVQUKH-UHFFFAOYSA-N 1,3-thiazole-4-carbonitrile Chemical compound N#CC1=CSC=N1 PNAFRZGWUVQUKH-UHFFFAOYSA-N 0.000 claims description 3
- RVOYDRUSMXEXNZ-UHFFFAOYSA-N 2-(2-chloropyridin-4-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound ClC1=NC=CC(=C1)N1C(C2(N(C(N(C(C2)=O)C2=C(C=C(C=C2F)C#CC2=CC=CC=C2)F)=O)CC1)C)=O RVOYDRUSMXEXNZ-UHFFFAOYSA-N 0.000 claims description 3
- AVFVNHLHJYTUFF-UHFFFAOYSA-N 2-(6-chloropyridin-3-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound ClC1=CC=C(C=N1)N1C(C2(N(C(N(C(C2)=O)C2=C(C=C(C=C2F)C#CC2=CC=CC=C2)F)=O)CC1)C)=O AVFVNHLHJYTUFF-UHFFFAOYSA-N 0.000 claims description 3
- WPCCZSWCCRKQDJ-UHFFFAOYSA-N 2-[(2-chlorophenyl)methyl]-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound ClC1=C(C=CC=C1)CN1C(C2(N(C(N(C(C2)=O)C2=C(C=C(C=C2F)C#CC2=CC=CC=C2)F)=O)CC1)C)=O WPCCZSWCCRKQDJ-UHFFFAOYSA-N 0.000 claims description 3
- QLRRBZJTTADZJZ-UHFFFAOYSA-N 2-[(3-chlorophenyl)methyl]-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound ClC=1C=C(C=CC=1)CN1C(C2(N(C(N(C(C2)=O)C2=C(C=C(C=C2F)C#CC2=CC=CC=C2)F)=O)CC1)C)=O QLRRBZJTTADZJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- JPVXJPBKZWTOCI-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(1,2-dimethylimidazol-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1N=C(N(C=1)C)C)=O)C)=O JPVXJPBKZWTOCI-UHFFFAOYSA-N 0.000 claims description 3
- IOPZDWKZGWNMOT-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(1,4-dimethylimidazol-2-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1N(C=C(N=1)C)C)=O)C)=O IOPZDWKZGWNMOT-UHFFFAOYSA-N 0.000 claims description 3
- MECMXQWENVPJRF-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2,5-dimethylpyrazol-3-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1N(N=C(C=1)C)C)=O)C)=O MECMXQWENVPJRF-UHFFFAOYSA-N 0.000 claims description 3
- WNWMENKSNHQYCD-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2,6-dimethylpyrimidin-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC(=NC(=C1)C)C)=O)C)=O WNWMENKSNHQYCD-UHFFFAOYSA-N 0.000 claims description 3
- JCZAEMOAMDPYGH-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(2,6-dimethylphenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC1=C(C=CC=C1C)C)=O)C)=O JCZAEMOAMDPYGH-UHFFFAOYSA-N 0.000 claims description 3
- XWCVWNPRBSIUOL-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-pyridin-2-yl-3,4,9,9a-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)C(N(CC2)C1=NC=CC=C1)=O)=O XWCVWNPRBSIUOL-UHFFFAOYSA-N 0.000 claims description 3
- WMFZELBIDWRSHT-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-pyrimidin-4-yl-3,4,9,9a-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)C(N(CC2)C1=NC=NC=C1)=O)=O WMFZELBIDWRSHT-UHFFFAOYSA-N 0.000 claims description 3
- VLZZBLBSGLKGEK-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylimidazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1N=CN(C=1)C)=O)C)=O VLZZBLBSGLKGEK-UHFFFAOYSA-N 0.000 claims description 3
- OZUGEOGFDBSBPW-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NN(C=C1)C)=O)C)=O OZUGEOGFDBSBPW-UHFFFAOYSA-N 0.000 claims description 3
- QVIUQFKHCCWVHD-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyridin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=CC(=NC=C1)C)=O)C)=O QVIUQFKHCCWVHD-UHFFFAOYSA-N 0.000 claims description 3
- XDMZEMBOQDFCNV-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC(=NC=C1)C)=O)C)=O XDMZEMBOQDFCNV-UHFFFAOYSA-N 0.000 claims description 3
- FJMWKWNOMQTEOZ-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(4-methyl-1,3-thiazol-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1SC=C(N=1)C)=O)C)=O FJMWKWNOMQTEOZ-UHFFFAOYSA-N 0.000 claims description 3
- IIDUGVVFBMEUHM-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methylpyridin-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC=C(C=1)C)=O)C)=O IIDUGVVFBMEUHM-UHFFFAOYSA-N 0.000 claims description 3
- OPDNGMKRSRAHNR-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methylpyrazin-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC(=CN=C1)C)=O)C)=O OPDNGMKRSRAHNR-UHFFFAOYSA-N 0.000 claims description 3
- RRCNNTURGMFUME-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methylpyridin-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC(=CC=C1)C)=O)C)=O RRCNNTURGMFUME-UHFFFAOYSA-N 0.000 claims description 3
- WRAAXDTZGPNLFW-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(pyridin-3-ylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC=1C=NC=CC=1)=O)C)=O WRAAXDTZGPNLFW-UHFFFAOYSA-N 0.000 claims description 3
- UXCLCEGMTSGHIG-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(pyridin-4-ylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC1=CC=NC=C1)=O)C)=O UXCLCEGMTSGHIG-UHFFFAOYSA-N 0.000 claims description 3
- KOZKEEIMNNOYJE-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[(1-methylpyrazol-4-yl)methyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC=1C=NN(C=1)C)=O)C)=O KOZKEEIMNNOYJE-UHFFFAOYSA-N 0.000 claims description 3
- LIMGPKFLKKKYCZ-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[(2-methylphenyl)methyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC1=C(C=CC=C1)C)=O)C)=O LIMGPKFLKKKYCZ-UHFFFAOYSA-N 0.000 claims description 3
- POQQFUZZKRJUNS-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[(4-methylphenyl)methyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC1=CC=C(C=C1)C)=O)C)=O POQQFUZZKRJUNS-UHFFFAOYSA-N 0.000 claims description 3
- YSRBYECRYISVDL-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[5-(trifluoromethyl)-1,3-thiazol-2-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1SC(=CN=1)C(F)(F)F)=O)C)=O YSRBYECRYISVDL-UHFFFAOYSA-N 0.000 claims description 3
- HSTARMKMXDEIBC-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC=CC=C1)=O)C)=O HSTARMKMXDEIBC-UHFFFAOYSA-N 0.000 claims description 3
- IHHPEUMEYXBBEF-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC=CC=N1)=O)C)=O IHHPEUMEYXBBEF-UHFFFAOYSA-N 0.000 claims description 3
- SXSFCMDTJHQNIM-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-5-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC=NC=1)=O)C)=O SXSFCMDTJHQNIM-UHFFFAOYSA-N 0.000 claims description 3
- AOVPEMHSGRLZAD-UHFFFAOYSA-N 7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound ClC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC=CC=C1)=O)C)=O AOVPEMHSGRLZAD-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- XVLKHJNRWVKPOB-LJAQVGFWSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(4-fluorophenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(CC1=CC=C(F)C=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 XVLKHJNRWVKPOB-LJAQVGFWSA-N 0.000 claims description 2
- NREGIORUDCVUML-SANMLTNESA-N (9aS)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1C=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(Cl)C=C(C=C1)C#CC1=CC=CC=C1 NREGIORUDCVUML-SANMLTNESA-N 0.000 claims description 2
- HGTGURNSYNFHEV-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(pyridin-2-ylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC1=NC=CC=C1)=O)C)=O HGTGURNSYNFHEV-UHFFFAOYSA-N 0.000 claims description 2
- VSIJLXLEQBQCOI-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[(3-methylphenyl)methyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC=1C=C(C=CC=1)C)=O)C)=O VSIJLXLEQBQCOI-UHFFFAOYSA-N 0.000 claims description 2
- TVKILMUJVJEALE-UHFFFAOYSA-N 7-[2-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C=CC(=C1)C#CC1=CC=CC=C1)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC=CC=1)=O)C)=O TVKILMUJVJEALE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 4
- 125000002947 alkylene group Chemical group 0.000 claims 2
- WPKMNZKULOFKEX-HHHXNRCGSA-N (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COC[C@@]12CC(=O)N(C(=O)N1CCN(C1=CN(C)N=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 WPKMNZKULOFKEX-HHHXNRCGSA-N 0.000 claims 1
- ONDDJVPUWJOWBR-VWLOTQADSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-methoxyethyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COCCN1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 ONDDJVPUWJOWBR-VWLOTQADSA-N 0.000 claims 1
- ULWQLDSWVKFUFC-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(3-methoxypropyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COCCCN1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 ULWQLDSWVKFUFC-SANMLTNESA-N 0.000 claims 1
- CVYCPZNYLXEPHX-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-(2-methylimidazol-1-yl)ethyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC1=NC=CN1CCN1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 CVYCPZNYLXEPHX-NDEPHWFRSA-N 0.000 claims 1
- LTKMTXLIAZLQHS-UHFFFAOYSA-N 1-methylpyridine Chemical compound CN1C=CC=C=C1 LTKMTXLIAZLQHS-UHFFFAOYSA-N 0.000 claims 1
- PQTYVNMMIPPCGF-UHFFFAOYSA-N 4-(trifluoromethyl)-1,3-thiazole Chemical compound FC(F)(F)C1=CSC=N1 PQTYVNMMIPPCGF-UHFFFAOYSA-N 0.000 claims 1
- WPKMNZKULOFKEX-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NN(C=1)C)=O)COC)=O WPKMNZKULOFKEX-UHFFFAOYSA-N 0.000 claims 1
- OWPUNVFFFSHRQU-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(4-methylpyridin-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC=CC(=C1)C)=O)C)=O OWPUNVFFFSHRQU-UHFFFAOYSA-N 0.000 claims 1
- QAZUXNIIDDPGSX-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(pyrimidin-4-ylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)CC1=NC=NC=C1)=O)C)=O QAZUXNIIDDPGSX-UHFFFAOYSA-N 0.000 claims 1
- DROIFRDBHCYWAA-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridazin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1N=NC=CC=1)=O)C)=O DROIFRDBHCYWAA-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 12
- 239000007787 solid Substances 0.000 description 148
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
- 239000000126 substance Substances 0.000 description 79
- 230000009471 action Effects 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- 238000006243 chemical reaction Methods 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 40
- DLHKOBKRNZFTKV-QFIPXVFZSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCNC2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 DLHKOBKRNZFTKV-QFIPXVFZSA-N 0.000 description 39
- DLHKOBKRNZFTKV-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O DLHKOBKRNZFTKV-UHFFFAOYSA-N 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 102100038354 Metabotropic glutamate receptor 4 Human genes 0.000 description 26
- 239000013058 crude material Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 108010038422 metabotropic glutamate receptor 4 Proteins 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 11
- DDOQBQRIEWHWBT-VKHMYHEASA-N (2S)-2-amino-4-phosphonobutanoic acid Chemical compound OC(=O)[C@@H](N)CCP(O)(O)=O DDOQBQRIEWHWBT-VKHMYHEASA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000000556 agonist Substances 0.000 description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 102100039087 Peptidyl-alpha-hydroxyglycine alpha-amidating lyase Human genes 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229920002401 polyacrylamide Polymers 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- XDELKSRGBLWMBA-UHFFFAOYSA-N 3-iodopyridine Chemical compound IC1=CC=CN=C1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 229910004298 SiO 2 Inorganic materials 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- WVPFUSDKZMRYGA-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2C(CC1)(C(NC(C2=O)=O)=O)C Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2C(CC1)(C(NC(C2=O)=O)=O)C WVPFUSDKZMRYGA-UHFFFAOYSA-N 0.000 description 5
- WVPFUSDKZMRYGA-QFIPXVFZSA-N FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2[C@@](CC1)(C(NC(C2=O)=O)=O)C Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2[C@@](CC1)(C(NC(C2=O)=O)=O)C WVPFUSDKZMRYGA-QFIPXVFZSA-N 0.000 description 5
- 101001032851 Homo sapiens Metabotropic glutamate receptor 4 Proteins 0.000 description 5
- PETMBWWTPCEEAJ-UHFFFAOYSA-N Nc1c(F)cc(cc1F)C#Cc1ccccc1 Chemical compound Nc1c(F)cc(cc1F)C#Cc1ccccc1 PETMBWWTPCEEAJ-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- JDLKAPUWSKAGLM-VWLOTQADSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1H-pyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CNN=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 JDLKAPUWSKAGLM-VWLOTQADSA-N 0.000 description 4
- PZXWUPDEBCZXBT-QFIPXVFZSA-N (9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCNC2=O)C1=C(F)C=C(C=C1F)C#CC1=C(F)C=CC=C1 PZXWUPDEBCZXBT-QFIPXVFZSA-N 0.000 description 4
- ZGEVJEQMVRIEPX-UHFFFAOYSA-N 3-bromo-1-methylpyrazole Chemical compound CN1C=CC(Br)=N1 ZGEVJEQMVRIEPX-UHFFFAOYSA-N 0.000 description 4
- SVOMOSXATZJWAF-UHFFFAOYSA-N 4-bromopyrimidine;hydrochloride Chemical compound Cl.BrC1=CC=NC=N1 SVOMOSXATZJWAF-UHFFFAOYSA-N 0.000 description 4
- GKVMMJSHJPLSRT-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3,4,9,9a-tetrahydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)C(NCC2)=O)=O GKVMMJSHJPLSRT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VRLHFARPTWGQLZ-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2C(CC1)(C(NC(C2=O)=O)=O)C Chemical compound ClC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2C(CC1)(C(NC(C2=O)=O)=O)C VRLHFARPTWGQLZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000003927 aminopyridines Chemical class 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 3
- ZXVDXDHKRHIVRF-QHCPKHFHSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC[C@@]12CC(=O)N(C(=O)N1CCNC2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 ZXVDXDHKRHIVRF-QHCPKHFHSA-N 0.000 description 3
- CKJQCLUHWBKJLT-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2-pyridin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=CN=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=C(F)C=CC=C1 CKJQCLUHWBKJLT-MHZLTWQESA-N 0.000 description 3
- WGFCNCNTGOFBBF-UHFFFAOYSA-N 2-bromopyrazine Chemical compound BrC1=CN=CC=N1 WGFCNCNTGOFBBF-UHFFFAOYSA-N 0.000 description 3
- RSDRDHPLXWMTRJ-UHFFFAOYSA-N 4-iodo-1-methylpyrazole Chemical compound CN1C=C(I)C=N1 RSDRDHPLXWMTRJ-UHFFFAOYSA-N 0.000 description 3
- ONPUDPQYQSTJNV-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-pyridin-3-yl-3,4,9,9a-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)C(N(CC2)C=1C=NC=CC=1)=O)=O ONPUDPQYQSTJNV-UHFFFAOYSA-N 0.000 description 3
- NFHOQAKVOKXGFO-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(NCC2)=O)COC)=O NFHOQAKVOKXGFO-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- 208000012661 Dyskinesia Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 3
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 3
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 description 3
- 230000001275 ca(2+)-mobilization Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- WAZMQENQHCRSBA-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(5-methoxypyrazin-2-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound COC1=NC=C(N=C1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 WAZMQENQHCRSBA-MHZLTWQESA-N 0.000 description 2
- VPRYGBDURNALQT-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC[C@@]12CC(=O)N(C(=O)N1CCN(C1=CN(C)N=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 VPRYGBDURNALQT-MHZLTWQESA-N 0.000 description 2
- TUQVRJJZUBDPPD-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-propan-2-ylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC(C)N1C=C(C=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 TUQVRJJZUBDPPD-NDEPHWFRSA-N 0.000 description 2
- XDMZEMBOQDFCNV-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC1=NC(=CC=N1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 XDMZEMBOQDFCNV-MHZLTWQESA-N 0.000 description 2
- CCZBJICMCCSFSN-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-oxo-1H-pyrimidin-5-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CN=C(O)N=C1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 CCZBJICMCCSFSN-SANMLTNESA-N 0.000 description 2
- IIDUGVVFBMEUHM-NDEPHWFRSA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methylpyridin-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC1=CN=CC(=C1)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 IIDUGVVFBMEUHM-NDEPHWFRSA-N 0.000 description 2
- RGGMDYZYUCLESN-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[(2-methylpyrazol-3-yl)methyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CN1N=CC=C1CN1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 RGGMDYZYUCLESN-MHZLTWQESA-N 0.000 description 2
- PABVBILCTRZZNG-MHZLTWQESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-methyl-1-(2,2,2-trifluoroethyl)imidazol-4-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC1=NC(=CN1CC(F)(F)F)N1CCN2C(=O)N(C(=O)C[C@@]2(C)C1=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 PABVBILCTRZZNG-MHZLTWQESA-N 0.000 description 2
- SGSSTGGHCKCAJI-SANMLTNESA-N (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCN(C1=CC=NC=N1)C2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 SGSSTGGHCKCAJI-SANMLTNESA-N 0.000 description 2
- XGLJSPFXMGSGKC-UHFFFAOYSA-N 1-bromo-1-methoxyethane Chemical compound COC(C)Br XGLJSPFXMGSGKC-UHFFFAOYSA-N 0.000 description 2
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 2
- RTMMSCJWQYWMNK-UHFFFAOYSA-N 2,2,2-trifluoroethyl trifluoromethanesulfonate Chemical compound FC(F)(F)COS(=O)(=O)C(F)(F)F RTMMSCJWQYWMNK-UHFFFAOYSA-N 0.000 description 2
- LSZMVESSGLHDJE-UHFFFAOYSA-N 2-bromo-4-methylpyridine Chemical compound CC1=CC=NC(Br)=C1 LSZMVESSGLHDJE-UHFFFAOYSA-N 0.000 description 2
- PGFIHORVILKHIA-UHFFFAOYSA-N 2-bromopyrimidine Chemical compound BrC1=NC=CC=N1 PGFIHORVILKHIA-UHFFFAOYSA-N 0.000 description 2
- KJKIPRQNFDUULB-UHFFFAOYSA-N 2-chloro-4-iodopyridine Chemical compound ClC1=CC(I)=CC=N1 KJKIPRQNFDUULB-UHFFFAOYSA-N 0.000 description 2
- QWLGCWXSNYKKDO-UHFFFAOYSA-N 2-chloro-5-iodopyridine Chemical compound ClC1=CC=C(I)C=N1 QWLGCWXSNYKKDO-UHFFFAOYSA-N 0.000 description 2
- HQQWKWWKAKZVFD-UHFFFAOYSA-N 2-fluoro-4-(2-phenylethynyl)aniline Chemical compound C1=C(F)C(N)=CC=C1C#CC1=CC=CC=C1 HQQWKWWKAKZVFD-UHFFFAOYSA-N 0.000 description 2
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 description 2
- ADCLTLQMVAEBLB-UHFFFAOYSA-N 3-bromo-5-methylpyridine Chemical compound CC1=CN=CC(Br)=C1 ADCLTLQMVAEBLB-UHFFFAOYSA-N 0.000 description 2
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 2
- OJPQVYZLQGRFSO-UHFFFAOYSA-N 4-bromo-2-methylpyrimidine Chemical compound CC1=NC=CC(Br)=N1 OJPQVYZLQGRFSO-UHFFFAOYSA-N 0.000 description 2
- GBPCCNWUSHSRTM-UHFFFAOYSA-N 4-bromo-6-methylpyrimidine Chemical compound CC1=CC(Br)=NC=N1 GBPCCNWUSHSRTM-UHFFFAOYSA-N 0.000 description 2
- VBLACOFEFKTGAS-UHFFFAOYSA-N 4-iodo-1-methyl-2h-pyridine Chemical compound CN1CC=C(I)C=C1 VBLACOFEFKTGAS-UHFFFAOYSA-N 0.000 description 2
- RTLUPHDWSUGAOS-UHFFFAOYSA-N 4-iodopyridine Chemical compound IC1=CC=NC=C1 RTLUPHDWSUGAOS-UHFFFAOYSA-N 0.000 description 2
- BTLMVZUBDGLVNM-UHFFFAOYSA-N 5-(bromomethyl)-1-methylpyrazole Chemical compound CN1N=CC=C1CBr BTLMVZUBDGLVNM-UHFFFAOYSA-N 0.000 description 2
- RJYWUQWCLZYCTI-UHFFFAOYSA-N 5-iodo-1-methylpyrazole Chemical compound CN1N=CC=C1I RJYWUQWCLZYCTI-UHFFFAOYSA-N 0.000 description 2
- NTXRNCUPGYOZCN-UHFFFAOYSA-N 5-iodo-2-methoxypyridine Chemical compound COC1=CC=C(I)C=N1 NTXRNCUPGYOZCN-UHFFFAOYSA-N 0.000 description 2
- MIQNXKWDQRNHAU-UHFFFAOYSA-N 5-methyl-n-(4-methylpyrimidin-2-yl)-4-(1h-pyrazol-4-yl)-1,3-thiazol-2-amine Chemical compound N=1C(C2=CNN=C2)=C(C)SC=1NC1=NC=CC(C)=N1 MIQNXKWDQRNHAU-UHFFFAOYSA-N 0.000 description 2
- USWMOXHOMVKAQC-UHFFFAOYSA-N 7-(2,6-difluoro-4-iodophenyl)-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)I)F)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O USWMOXHOMVKAQC-UHFFFAOYSA-N 0.000 description 2
- FZSXHTPPCUENBZ-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(6-methoxypyridin-3-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC(=CC=1)OC)=O)C)=O FZSXHTPPCUENBZ-UHFFFAOYSA-N 0.000 description 2
- FKNYWDGKQSQKTP-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1,3-thiazol-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1SC=CN=1)=O)C)=O FKNYWDGKQSQKTP-UHFFFAOYSA-N 0.000 description 2
- QPMZDQLPIGCTRA-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NN(C=1)C)=O)C)=O QPMZDQLPIGCTRA-UHFFFAOYSA-N 0.000 description 2
- XMXJHRSYTJPWIV-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1N(N=CC=1)C)=O)C)=O XMXJHRSYTJPWIV-UHFFFAOYSA-N 0.000 description 2
- VKFZLAAEVPSTQP-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methyl-1,3-thiazol-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1SC(=CN=1)C)=O)C)=O VKFZLAAEVPSTQP-UHFFFAOYSA-N 0.000 description 2
- HTFIHEGPJFNUIX-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methylpyridin-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1C=NC(=CC=1)C)=O)C)=O HTFIHEGPJFNUIX-UHFFFAOYSA-N 0.000 description 2
- UVSXAALHOYAJTC-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C=1SC=C(N=1)C(F)(F)F)=O)C)=O UVSXAALHOYAJTC-UHFFFAOYSA-N 0.000 description 2
- SGSSTGGHCKCAJI-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(N(CC2)C1=NC=NC=C1)=O)C)=O SGSSTGGHCKCAJI-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KOVFDWDJFSHYIM-UHFFFAOYSA-N ClC1=C(N)C(=CC(=C1)C#CC1=CC=CC=C1)F Chemical compound ClC1=C(N)C(=CC(=C1)C#CC1=CC=CC=C1)F KOVFDWDJFSHYIM-UHFFFAOYSA-N 0.000 description 2
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 108010027915 Glutamate Receptors Proteins 0.000 description 2
- 102000018899 Glutamate Receptors Human genes 0.000 description 2
- 102100030668 Glutamate receptor 4 Human genes 0.000 description 2
- 101710087627 Glutamate receptor 4 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ODRRRUXBCFWTCE-UHFFFAOYSA-N Nc1ccc(cc1Cl)C#Cc1ccccc1 Chemical compound Nc1ccc(cc1Cl)C#Cc1ccccc1 ODRRRUXBCFWTCE-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 210000000063 presynaptic terminal Anatomy 0.000 description 2
- ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000011808 rodent model Methods 0.000 description 2
- 238000012106 screening analysis Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 210000003523 substantia nigra Anatomy 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- FPXPIEZPAXSELW-CYVLTUHYSA-N (7e)-7-hydroxyimino-n-phenyl-1,7a-dihydrocyclopropa[b]chromene-1a-carboxamide Chemical compound O1C2=CC=CC=C2C(=N/O)/C2CC21C(=O)NC1=CC=CC=C1 FPXPIEZPAXSELW-CYVLTUHYSA-N 0.000 description 1
- ZXVDXDHKRHIVRF-HSZRJFAPSA-N (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound CC[C@]12CC(=O)N(C(=O)N1CCNC2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 ZXVDXDHKRHIVRF-HSZRJFAPSA-N 0.000 description 1
- DLHKOBKRNZFTKV-JOCHJYFZSA-N (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@]12CC(=O)N(C(=O)N1CCNC2=O)C1=C(F)C=C(C=C1F)C#CC1=CC=CC=C1 DLHKOBKRNZFTKV-JOCHJYFZSA-N 0.000 description 1
- PZXWUPDEBCZXBT-JOCHJYFZSA-N (9aR)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@]12CC(=O)N(C(=O)N1CCNC2=O)C1=C(F)C=C(C=C1F)C#CC1=C(F)C=CC=C1 PZXWUPDEBCZXBT-JOCHJYFZSA-N 0.000 description 1
- IACXOUDLXGOWDI-QFIPXVFZSA-N (9aS)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound C[C@@]12CC(=O)N(C(=O)N1CCNC2=O)C1=C(Cl)C=C(C=C1)C#CC1=CC=CC=C1 IACXOUDLXGOWDI-QFIPXVFZSA-N 0.000 description 1
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 1
- RBACIKXCRWGCBB-UHFFFAOYSA-N 1,2-Epoxybutane Chemical compound CCC1CO1 RBACIKXCRWGCBB-UHFFFAOYSA-N 0.000 description 1
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- IFEOSQZAGJFBDF-UHFFFAOYSA-N 1-(2-bromoethyl)-2-methylimidazole;hydrobromide Chemical compound Br.CC1=NC=CN1CCBr IFEOSQZAGJFBDF-UHFFFAOYSA-N 0.000 description 1
- PURSZYWBIQIANP-UHFFFAOYSA-N 1-(bromomethyl)-2-chlorobenzene Chemical compound ClC1=CC=CC=C1CBr PURSZYWBIQIANP-UHFFFAOYSA-N 0.000 description 1
- FFWQLZFIMNTUCZ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CBr FFWQLZFIMNTUCZ-UHFFFAOYSA-N 0.000 description 1
- WGVYCXYGPNNUQA-UHFFFAOYSA-N 1-(bromomethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CBr WGVYCXYGPNNUQA-UHFFFAOYSA-N 0.000 description 1
- LZIYAIRGDHSVED-UHFFFAOYSA-N 1-(bromomethyl)-3-chlorobenzene Chemical compound ClC1=CC=CC(CBr)=C1 LZIYAIRGDHSVED-UHFFFAOYSA-N 0.000 description 1
- WZRKSPFYXUXINF-UHFFFAOYSA-N 1-(bromomethyl)-4-methylbenzene Chemical compound CC1=CC=C(CBr)C=C1 WZRKSPFYXUXINF-UHFFFAOYSA-N 0.000 description 1
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- XWZIDZDMNYAEOP-UHFFFAOYSA-N 1-ethyl-4-iodopyrazole Chemical compound CCN1C=C(I)C=N1 XWZIDZDMNYAEOP-UHFFFAOYSA-N 0.000 description 1
- YFPQIXUNBPQKQR-UHFFFAOYSA-N 1-ethynyl-2-fluorobenzene Chemical compound FC1=CC=CC=C1C#C YFPQIXUNBPQKQR-UHFFFAOYSA-N 0.000 description 1
- BAXVQKUKLDTROZ-VMPITWQZSA-N 1-methoxy-3-[(E)-3-phenylprop-2-enoxy]propan-2-ol Chemical compound C(\C=C\C1=CC=CC=C1)OCC(COC)O BAXVQKUKLDTROZ-VMPITWQZSA-N 0.000 description 1
- HIQNROHAJOOINQ-VMPITWQZSA-N 1-methoxy-3-[(E)-3-phenylprop-2-enoxy]propan-2-one Chemical compound COCC(=O)COC\C=C\C1=CC=CC=C1 HIQNROHAJOOINQ-VMPITWQZSA-N 0.000 description 1
- WOGOXEPEEXSPAF-UHFFFAOYSA-N 1h-imidazole;piperidine Chemical class C1=CNC=N1.C1CCNCC1 WOGOXEPEEXSPAF-UHFFFAOYSA-N 0.000 description 1
- HCUZNQLIMDDCHF-UHFFFAOYSA-N 2,6-difluoro-4-iodoaniline Chemical compound NC1=C(F)C=C(I)C=C1F HCUZNQLIMDDCHF-UHFFFAOYSA-N 0.000 description 1
- PSRARXVEBZQEML-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1CBr PSRARXVEBZQEML-UHFFFAOYSA-N 0.000 description 1
- JQDNCGRNPYKRAO-UHFFFAOYSA-N 2-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=CC=N1 JQDNCGRNPYKRAO-UHFFFAOYSA-N 0.000 description 1
- LKMJVFRMDSNFRT-UHFFFAOYSA-N 2-(methoxymethyl)oxirane Chemical compound COCC1CO1 LKMJVFRMDSNFRT-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 1
- HTVHRNHOLJNKNO-UHFFFAOYSA-N 2-bromo-1,3-thiazole-4-carbonitrile Chemical compound BrC1=NC(C#N)=CS1 HTVHRNHOLJNKNO-UHFFFAOYSA-N 0.000 description 1
- JKVMBWITGAWCIG-UHFFFAOYSA-N 2-bromo-1,4-dimethylimidazole Chemical compound CC1=CN(C)C(Br)=N1 JKVMBWITGAWCIG-UHFFFAOYSA-N 0.000 description 1
- NZNVGMVYUYNBOM-UHFFFAOYSA-N 2-bromo-4-(trifluoromethyl)-1,3-thiazole Chemical compound FC(F)(F)C1=CSC(Br)=N1 NZNVGMVYUYNBOM-UHFFFAOYSA-N 0.000 description 1
- KLFWJAAGXUDNIS-UHFFFAOYSA-N 2-bromo-4-methyl-1,3-thiazole Chemical compound CC1=CSC(Br)=N1 KLFWJAAGXUDNIS-UHFFFAOYSA-N 0.000 description 1
- UFZHUWFGWBQZTL-UHFFFAOYSA-N 2-bromo-5-(trifluoromethyl)-1,3-thiazole Chemical compound FC(F)(F)C1=CN=C(Br)S1 UFZHUWFGWBQZTL-UHFFFAOYSA-N 0.000 description 1
- YMDHKDFBWIRZAZ-UHFFFAOYSA-N 2-bromo-5-methoxypyrazine Chemical compound COC1=CN=C(Br)C=N1 YMDHKDFBWIRZAZ-UHFFFAOYSA-N 0.000 description 1
- FJPZHYAYNAUKKA-UHFFFAOYSA-N 2-bromo-5-methyl-1,3-thiazole Chemical compound CC1=CN=C(Br)S1 FJPZHYAYNAUKKA-UHFFFAOYSA-N 0.000 description 1
- APTDXZWQIHBNTO-UHFFFAOYSA-N 2-bromo-5-phenylmethoxypyrazine Chemical compound C1=NC(Br)=CN=C1OCC1=CC=CC=C1 APTDXZWQIHBNTO-UHFFFAOYSA-N 0.000 description 1
- SOHDPICLICFSOP-UHFFFAOYSA-N 2-bromo-6-methylpyridine Chemical compound CC1=CC=CC(Br)=N1 SOHDPICLICFSOP-UHFFFAOYSA-N 0.000 description 1
- IZQAUUVBKYXMET-UHFFFAOYSA-N 2-bromoethanamine Chemical class NCCBr IZQAUUVBKYXMET-UHFFFAOYSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- MYDAOWXYGPEPJT-UHFFFAOYSA-N 2-chloro-4-iodoaniline Chemical compound NC1=CC=C(I)C=C1Cl MYDAOWXYGPEPJT-UHFFFAOYSA-N 0.000 description 1
- MBOVEKLHHKYVAH-UHFFFAOYSA-N 2-chloro-6-fluoro-4-iodoaniline Chemical compound NC1=C(F)C=C(I)C=C1Cl MBOVEKLHHKYVAH-UHFFFAOYSA-N 0.000 description 1
- CUMTUBVTKOYYOU-UHFFFAOYSA-N 2-fluoro-4-iodoaniline Chemical compound NC1=CC=C(I)C=C1F CUMTUBVTKOYYOU-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- AYTUNLVSFHHZHJ-UHFFFAOYSA-N 2h-pyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound O=C1NC(=O)C=C2N1C=CNC2=O AYTUNLVSFHHZHJ-UHFFFAOYSA-N 0.000 description 1
- FNHPUOJKUXFUKN-UHFFFAOYSA-N 3-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=CN=C1 FNHPUOJKUXFUKN-UHFFFAOYSA-N 0.000 description 1
- QFRURJKLPJVRQY-UHFFFAOYSA-N 3-Aminopentanoic acid Chemical compound CCC(N)CC(O)=O QFRURJKLPJVRQY-UHFFFAOYSA-N 0.000 description 1
- CAEPGFNWRQDVRV-UHFFFAOYSA-N 3-iodo-1-methyl-1,2,4-triazole Chemical compound CN1C=NC(I)=N1 CAEPGFNWRQDVRV-UHFFFAOYSA-N 0.000 description 1
- YJLFNBXIOWKHID-UHFFFAOYSA-N 3-iodo-6-methylpyridazine Chemical compound CC1=CC=C(I)N=N1 YJLFNBXIOWKHID-UHFFFAOYSA-N 0.000 description 1
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 description 1
- OCDRKUKNEBBPJH-UHFFFAOYSA-N 4-(2-bromoethyl)-1-methylpyrazole Chemical compound CN1C=C(CCBr)C=N1 OCDRKUKNEBBPJH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JUAZMXHMICDXKH-UHFFFAOYSA-N 4-(bromomethyl)-1-methylpyrazole;hydrobromide Chemical compound Br.CN1C=C(CBr)C=N1 JUAZMXHMICDXKH-UHFFFAOYSA-N 0.000 description 1
- VAJUUDUWDNCECT-UHFFFAOYSA-N 4-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=NC=C1 VAJUUDUWDNCECT-UHFFFAOYSA-N 0.000 description 1
- POXGELXMMJWSRC-UHFFFAOYSA-N 4-(bromomethyl)pyrimidine;hydrobromide Chemical compound Br.BrCC1=CC=NC=N1 POXGELXMMJWSRC-UHFFFAOYSA-N 0.000 description 1
- FZRKTLGQQTWOMJ-UHFFFAOYSA-N 4-bromo-1,2-dimethylimidazole Chemical compound CC1=NC(Br)=CN1C FZRKTLGQQTWOMJ-UHFFFAOYSA-N 0.000 description 1
- IOTSLMMLLXTNNH-UHFFFAOYSA-N 4-bromo-1-methylimidazole Chemical compound CN1C=NC(Br)=C1 IOTSLMMLLXTNNH-UHFFFAOYSA-N 0.000 description 1
- PTCKNLGMBFKIFP-UHFFFAOYSA-N 4-bromo-2,6-dimethylpyrimidine Chemical compound CC1=CC(Br)=NC(C)=N1 PTCKNLGMBFKIFP-UHFFFAOYSA-N 0.000 description 1
- JFBMFWHEXBLFCR-UHFFFAOYSA-N 4-bromo-2-methylpyridine Chemical compound CC1=CC(Br)=CC=N1 JFBMFWHEXBLFCR-UHFFFAOYSA-N 0.000 description 1
- AQVBKYCOAWEBAY-UHFFFAOYSA-N 4-bromo-3,5-dimethylpyridine;hydrochloride Chemical compound Cl.CC1=CN=CC(C)=C1Br AQVBKYCOAWEBAY-UHFFFAOYSA-N 0.000 description 1
- BSDGZUDFPKIYQG-UHFFFAOYSA-N 4-bromopyridine Chemical compound BrC1=CC=NC=C1 BSDGZUDFPKIYQG-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- CFXNVDUEBJYAAZ-UHFFFAOYSA-N 4-iodo-1-propan-2-ylpyrazole Chemical compound CC(C)N1C=C(I)C=N1 CFXNVDUEBJYAAZ-UHFFFAOYSA-N 0.000 description 1
- GGSVXDGOBFDIRX-UHFFFAOYSA-N 4-iodo-2-methyl-1-(2,2,2-trifluoroethyl)imidazole Chemical compound CC1=NC(I)=CN1CC(F)(F)F GGSVXDGOBFDIRX-UHFFFAOYSA-N 0.000 description 1
- XJWYFEQOMPSWAG-UHFFFAOYSA-N 5-(2-bromoethyl)-1-methylpyrazole Chemical compound CN1N=CC=C1CCBr XJWYFEQOMPSWAG-UHFFFAOYSA-N 0.000 description 1
- MGDIZQXZNAILTO-UHFFFAOYSA-N 5-bromo-1,3-dimethylpyrazole Chemical compound CC=1C=C(Br)N(C)N=1 MGDIZQXZNAILTO-UHFFFAOYSA-N 0.000 description 1
- HHVFVHIUOMMWRN-UHFFFAOYSA-N 5-bromo-1-methylpyridin-2-one Chemical compound CN1C=C(Br)C=CC1=O HHVFVHIUOMMWRN-UHFFFAOYSA-N 0.000 description 1
- ZQGCPSLVRMJUNM-UHFFFAOYSA-N 5-bromo-2-cyclopropyloxypyrimidine Chemical compound N1=CC(Br)=CN=C1OC1CC1 ZQGCPSLVRMJUNM-UHFFFAOYSA-N 0.000 description 1
- GNSREVHIXMTHFA-UHFFFAOYSA-N 5-bromo-2-ethoxypyrimidine Chemical compound CCOC1=NC=C(Br)C=N1 GNSREVHIXMTHFA-UHFFFAOYSA-N 0.000 description 1
- DWVCZDMMGYIULX-UHFFFAOYSA-N 5-bromo-2-methoxypyrimidine Chemical compound COC1=NC=C(Br)C=N1 DWVCZDMMGYIULX-UHFFFAOYSA-N 0.000 description 1
- OFKWIQJLYCKDNY-UHFFFAOYSA-N 5-bromo-2-methylpyridine Chemical compound CC1=CC=C(Br)C=N1 OFKWIQJLYCKDNY-UHFFFAOYSA-N 0.000 description 1
- RDGZEALFIOPSCC-UHFFFAOYSA-N 5-bromo-2-phenylmethoxypyrimidine Chemical compound N1=CC(Br)=CN=C1OCC1=CC=CC=C1 RDGZEALFIOPSCC-UHFFFAOYSA-N 0.000 description 1
- BEBHDGQMLLXGDG-UHFFFAOYSA-N 5-bromo-2-propan-2-yloxypyrimidine Chemical compound CC(C)OC1=NC=C(Br)C=N1 BEBHDGQMLLXGDG-UHFFFAOYSA-N 0.000 description 1
- GYCPLYCTMDTEPU-UHFFFAOYSA-N 5-bromopyrimidine Chemical compound BrC1=CN=CN=C1 GYCPLYCTMDTEPU-UHFFFAOYSA-N 0.000 description 1
- CAUOGRQSEBXVFL-UHFFFAOYSA-N 6-bromo-2-methyl-2H-pyrazin-3-one Chemical compound CC1N=C(Br)C=NC1=O CAUOGRQSEBXVFL-UHFFFAOYSA-N 0.000 description 1
- ZXVDXDHKRHIVRF-UHFFFAOYSA-N 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(NCC2)=O)CC)=O ZXVDXDHKRHIVRF-UHFFFAOYSA-N 0.000 description 1
- PZXWUPDEBCZXBT-UHFFFAOYSA-N 7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C(=CC(=C1)C#CC1=C(C=CC=C1)F)F)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O PZXWUPDEBCZXBT-UHFFFAOYSA-N 0.000 description 1
- IACXOUDLXGOWDI-UHFFFAOYSA-N 7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound ClC1=C(C=CC(=C1)C#CC1=CC=CC=C1)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O IACXOUDLXGOWDI-UHFFFAOYSA-N 0.000 description 1
- ZCGJFMMEXIDMFF-UHFFFAOYSA-N 7-[2-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione Chemical compound FC1=C(C=CC(=C1)C#CC1=CC=CC=C1)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O ZCGJFMMEXIDMFF-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- REMFBDOPUGHANF-UHFFFAOYSA-N C1CN(C(=O)C2N1C(=O)NC(=O)C2)C3=CC=NC=C3 Chemical compound C1CN(C(=O)C2N1C(=O)NC(=O)C2)C3=CC=NC=C3 REMFBDOPUGHANF-UHFFFAOYSA-N 0.000 description 1
- RNQNDUDOXSNFAJ-WEVVVXLNSA-N COCC(=O)CC\C=C\C1=CC=CC=C1 Chemical compound COCC(=O)CC\C=C\C1=CC=CC=C1 RNQNDUDOXSNFAJ-WEVVVXLNSA-N 0.000 description 1
- LZJJCCSGWKTYFJ-WEVVVXLNSA-N COCC(O)CC\C=C\C1=CC=CC=C1 Chemical compound COCC(O)CC\C=C\C1=CC=CC=C1 LZJJCCSGWKTYFJ-WEVVVXLNSA-N 0.000 description 1
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- JLRCGNHABLCPLD-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O Chemical compound ClC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N2C(CC1=O)(C(NCC2)=O)C)=O JLRCGNHABLCPLD-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- UHXXGTVWFNSLNV-MHZLTWQESA-N FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2[C@@](CC1)(C(N(C(C2=O)=O)C=2C=NC(=NC2)OC)=O)C Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN2[C@@](CC1)(C(N(C(C2=O)=O)C=2C=NC(=NC2)OC)=O)C UHXXGTVWFNSLNV-MHZLTWQESA-N 0.000 description 1
- NIXAAOYIVFZBSD-UHFFFAOYSA-N FC1=C(C=CC(=C1)C#CC1=CC=CC=C1)N1CN2C(CC1)(C(NC(C2=O)=O)=O)C Chemical compound FC1=C(C=CC(=C1)C#CC1=CC=CC=C1)N1CN2C(CC1)(C(NC(C2=O)=O)=O)C NIXAAOYIVFZBSD-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 102000034354 Gi proteins Human genes 0.000 description 1
- 108091006101 Gi proteins Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101150025480 Grm4 gene Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001032837 Homo sapiens Metabotropic glutamate receptor 6 Proteins 0.000 description 1
- 101001027295 Homo sapiens Metabotropic glutamate receptor 8 Proteins 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102100038300 Metabotropic glutamate receptor 6 Human genes 0.000 description 1
- 102100038294 Metabotropic glutamate receptor 7 Human genes 0.000 description 1
- 102100037636 Metabotropic glutamate receptor 8 Human genes 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 150000000475 acetylene derivatives Chemical class 0.000 description 1
- QOMNQGZXFYNBNG-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-difluoro-6-oxoxanthen-9-yl]-2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-methylanilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C2=C3C=C(F)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(F)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O QOMNQGZXFYNBNG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 229930189065 blasticidin Natural products 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000009933 burial Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012578 cell culture reagent Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 description 1
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229940052764 dopaminergic anti-parkinson drug mao b inhibitors Drugs 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- SNAYAOANCLLJCP-QGSAOVALSA-N ethyl (Z)-3-(methoxymethyl)-4-[(E)-3-phenylprop-2-enoxy]but-2-enoate Chemical compound C(\C=C\C1=CC=CC=C1)OC\C(=C/C(=O)OCC)\COC SNAYAOANCLLJCP-QGSAOVALSA-N 0.000 description 1
- HNYRNJAZRKCHSC-UHFFFAOYSA-N ethyl 2-(3-oxopiperazin-2-yl)acetate Chemical compound CCOC(=O)CC1NCCNC1=O HNYRNJAZRKCHSC-UHFFFAOYSA-N 0.000 description 1
- GLEMXNLSKLWVSW-UHFFFAOYSA-N ethyl 2-methoxybutanoate Chemical compound CCOC(=O)C(CC)OC GLEMXNLSKLWVSW-UHFFFAOYSA-N 0.000 description 1
- VFNCZOZLBUASEW-JXMROGBWSA-N ethyl 3-amino-3-(methoxymethyl)-4-[(E)-3-phenylprop-2-enoxy]butanoate Chemical compound NC(CC(=O)OCC)(COC)COC\C=C\C1=CC=CC=C1 VFNCZOZLBUASEW-JXMROGBWSA-N 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- AGMKVZDPATUSMS-UHFFFAOYSA-N ethyl pent-2-enoate Chemical compound CCOC(=O)C=CCC AGMKVZDPATUSMS-UHFFFAOYSA-N 0.000 description 1
- 230000036749 excitatory postsynaptic potential Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000036734 inhibitory postsynaptic potential Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 108010038449 metabotropic glutamate receptor 7 Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000023187 negative regulation of glucagon secretion Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- YIYBQIKDCADOSF-UHFFFAOYSA-N pent-2-enoic acid Chemical compound CCC=CC(O)=O YIYBQIKDCADOSF-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 230000006416 presynaptic localization Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- SLLXGLWEDVXNEA-UHFFFAOYSA-N tert-butyl pyrimidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=NC=CC=N1 SLLXGLWEDVXNEA-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- DDMOZUBZYFKJDS-UHFFFAOYSA-N triphenyl(propylidene)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CCC)C1=CC=CC=C1 DDMOZUBZYFKJDS-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Abstract
本發明係關於式I化合物
其中R1、L、R2、R3、R4及Y係如說明書中所定義,或其醫藥上可接受的鹽或酸加成鹽、外消旋混合物或其相應的對映異構體及/或光學異構體及/或立體異構體。 Where R 1 , L, R 2 , R 3 , R 4 and Y are as defined in the specification, or a pharmaceutically acceptable salt or acid addition salt thereof, a racemic mixture or the corresponding enantiomer And / or optical isomers and / or stereoisomers.
該等化合物可用於治療帕金森氏病(Parkinson's disease)、焦慮、嘔吐、強迫症、自閉症、神經保護、癌症、抑鬱及2型糖尿病。 These compounds are useful in the treatment of Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, autism, neuroprotection, cancer, depression, and type 2 diabetes.
Description
本發明係關於式(I)之化合物
其中R1係氫、F或Cl;L係鍵或低碳數伸烷基;R2為-(CH2)nO-低碳數烷基、經鹵素取代之低碳數烷基、-(CH2)nC(O)O-低碳數烷基、經低碳數烷基或鹵素取代之苯基,或者為選自吡啶基、嘧啶基、嗒嗪基、噻唑基、咪唑基、吡唑基或三唑基的5或6-員雜芳基,其等視情況經低碳數烷基、鹵素、低碳數烷氧基、=O、苄氧基、環烷氧基、羥基、氰基、經鹵素取代之低碳數烷基、或經-(CH2)nO-低碳數烷基取代;n為1、2或3;R3為氫、低碳數烷基或-(CH2)nO-低碳數烷基;R4為視情況經F取代之苯基、吡啶基或嘧啶基;Y為CF或CCl;或其醫藥上可接受的鹽或酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體及/或立體異構體。 Where R 1 is hydrogen, F or Cl; L is a bond or a low-carbon alkylene; R 2 is-(CH 2 ) n O-low-carbon alkyl, a halogen-substituted low-carbon alkyl,-( CH 2 ) n C (O) O-lower alkyl, phenyl substituted with lower alkyl or halogen, or selected from pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, pyr 5 or 6-membered heteroaryl of oxazolyl or triazolyl, optionally via a lower alkyl, halogen, lower alkoxy, = 0, benzyloxy, cycloalkoxy, hydroxyl, Cyano, halogen-substituted lower alkyl, or-(CH 2 ) n O-lower alkyl; n is 1, 2 or 3; R 3 is hydrogen, lower alkyl or- (CH 2 ) n O-low carbon number alkyl; R 4 is phenyl, pyridyl or pyrimidinyl optionally substituted with F; Y is CF or CCl; or a pharmaceutically acceptable salt or acid addition salt thereof , Racemic mixtures or their corresponding enantiomers and / or optical isomers and / or stereoisomers.
現已驚人地發現,通式I之化合物係代謝型麩胺酸受體4(mGluR4)之正向異位調節劑(PAM)。 It has now surprisingly been discovered that compounds of general formula I are positive ectopic modulators (PAM) of metabotropic glutamate receptor 4 (mGluR4).
代謝型麩胺酸受體4係一種在人類中由GRM4基因編碼之蛋白質。 Metabolic glutamate receptor 4 is a protein encoded by the GRM4 gene in humans.
連同GRM6、GRM7及GRM8,其屬於代謝型麩胺酸受體家族之III組,且係經由Gαi/o蛋白質之活化而負向偶合至腺苷酸環化酶。其主要表現於突觸前末梢,作為自身受體或雜受體(heteroceptor)起作用且其活化導致從突觸前末梢釋放之遞質減少。mGluR4目前正受到許多關注,主要基於其獨特分佈且最近的證據表明,此受體的活化在許多CNS及非CNS路徑中起著關鍵調節作用(Celanire S,Campo B,Expert Opinion in Drug Discovery,2012)。 Together with GRM6, GRM7, and GRM8, it belongs to group III of the metabolic glutamate receptor family and is negatively coupled to adenylate cyclase via the activation of Gαi / o protein. It is mainly manifested in the presynaptic terminal, acting as an autoreceptor or heteroceptor, and its activation results in a decrease in transmitter release from the presynaptic terminal. mGluR4 is currently receiving a lot of attention, mainly based on its unique distribution and recent evidence that this receptor activation plays a key regulatory role in many CNS and non-CNS pathways ( Celanire S, Campo B, Expert Opinion in Drug Discovery, 2012 ).
III組mGluR的配體結合結構域中的相似性產生用於識別該受體之選擇性正位激動劑的一個挑戰,雖然在該領域已經取得了一些進展。然而,靶向正向異位調節劑(PAM)而非正位激動劑提供可識別mGluR之間具唯一選擇性之分子的更廣泛機會。 The similarity in the ligand binding domains of group III mGluRs creates a challenge for identifying selective orthotopic agonists for this receptor, although some progress has been made in this area. However, targeting forward ectopic modulators (PAMs) rather than orthotopic agonists provides a broader opportunity to identify molecules with unique selectivity between mGluRs.
mGluR4 PAM正在成為用於治療運動(及非運動)症狀的有前途的標靶,以及經由非多巴胺能途徑在帕金森氏病中的疾病修飾劑。 mGluR4 PAM is becoming a promising target for the treatment of motor (and non-motor) symptoms and disease modifiers in Parkinson's disease via non-dopaminergic pathways.
帕金森氏病是一種進行性神經退化性疾病,其導致多巴胺能神經元在黑質(SN)中的損失。在該疾病中多巴胺耗竭的一個後果係一系列運動障礙,包括運動遲緩、運動不能、震顫、步態紊亂及平衡問題。此等運動障礙形成PD的標誌,雖然有與該疾病相關聯的許多其他非運動症狀。在該疾病的早期過程中,PD症狀有效地經多巴胺更換或增強而得到治療,其中使用多巴胺D2受體激動劑、左旋多巴或單胺氧化酶B抑制劑。然而,隨著該疾病進展,此等藥劑在控制運動症狀方面變得不太有效。此外,其之使用受出現不利影響,包括多巴胺激動劑引起之運動障礙的限制。因此,仍然需要治療PD的新方 法,其改善運動症狀控制的有效性。 Parkinson's disease is a progressive neurodegenerative disease that results in the loss of dopaminergic neurons in the substantia nigra (SN). One consequence of dopamine depletion in the disease is a series of dyskinesias, including bradykinesia, inability to move, tremors, gait disorders and balance problems. These dyskinesias form a hallmark of PD, although there are many other non-motor symptoms associated with the disease. In the early stages of the disease, PD symptoms are effectively treated by dopamine replacement or enhancement, using dopamine D2 receptor agonists, levodopa or monoamine oxidase B inhibitors. However, as the disease progresses, these agents become less effective in controlling motor symptoms. In addition, its use is adversely affected by the appearance, including limitation of dyskinesia caused by dopamine agonists. Therefore, there is still a need for new treatments for PD Method, which improves the effectiveness of the control of motor symptoms.
已提出代謝型麩胺酸受體4(mGluR4)之活化作為一種潛在的帕金森氏病之治療方法。作為III組mGluR的一員,mGluR4主要係突觸前麩胺酸受體,該受體在控制運動的基底節電路中之若干個關鍵位置中表現。以偏好III組之激動劑活化mGluR4減少抑制性及興奮性突觸後電位,大概分別藉由減少GABA及麩胺酸的釋放所致。 Activation of metabolic glutamate receptor 4 (mGluR4) has been proposed as a potential treatment for Parkinson's disease. As a member of group III mGluR, mGluR4 is mainly a presynaptic glutamate receptor that is expressed in several key positions in the basal ganglia circuit that control movement. Activating mGluR4 with group III agonists to reduce inhibitory and excitatory post-synaptic potentials is probably caused by reducing the release of GABA and glutamic acid, respectively.
針對緩解帕金森運動症狀同時衰減黑質紋狀體神經元之持續變性的新穎藥物的搜索係特別受關注。已經證明正位mGluR4激動劑L-AP4在PD之6-OHDA囓齒動物模型中之神經保護效應且第一正向異位調節劑(-)-PHCCC減少經1-甲基-4-苯基-1,2,3,6-四氫吡啶(MPTP)處理之小鼠中的黑質紋狀體變性。彼等研究提供臨床前證據表明,mGluR4活化劑構成一種不僅對PD的對症治療,而且潛在地作為疾病修飾劑的堅實方法。 The search for novel drugs that alleviate Parkinson's motor symptoms while attenuating the persistent degeneration of nigrostriatal neurons is of particular interest. The neuroprotective effect of orthotopic mGluR4 agonist L-AP4 in a 6-OHDA rodent model of PD has been demonstrated and the first forward ectopic modulator (-)-PHCCC is reduced by 1-methyl-4-phenyl- Nigra striatal degeneration in 1,2,3,6-tetrahydropyridine (MPTP) treated mice. Their studies provide preclinical evidence that mGluR4 activators constitute a solid approach not only for the symptomatic treatment of PD, but also potentially as a disease modifier.
選擇性mGluR4激動劑之神經保護效應亦描述於以下中:Neuroreport,19(4),475-8,2008,Proc.Natl.Acad.Sci,USA,100(23),13668-73,2003及J.Neurosci.26(27),7222-9,2006及Mol.Pharmacol.74(5),1345-58,2008。 The neuroprotective effects of selective mGluR4 agonists are also described in Neuroreport, 19 (4), 475-8, 2008, Proc. Natl. Acad. Sci, USA, 100 (23), 13668-73, 2003, and J Neurosci. 26 (27), 7222-9, 2006 and Mol. Pharmacol. 74 (5), 1345-58, 2008.
焦慮症係世界上最普遍的精神病症之一,並且係與帕金森氏病共同病態(Prediger R等人,Neuropharmacology 2012;62:115-24)。過量麩胺酸能神經傳遞係焦慮病理生理的一個重要特徵。基於mGluR4在涉及焦慮及情緒障礙之腦區中的突觸前定位,及衰減過度大腦興奮,mGluR4活化劑可代表新一代抗焦慮治療劑(Eur.J.Pharmacol.,498(1-3),153-6,2004)。 Anxiety disorder is one of the most prevalent mental disorders in the world and is co-morbid with Parkinson's disease ( Prediger R et al., Neuropharmacology 2012; 62: 115-24) . Excessive glutamate neurotransmission system is an important feature of anxiety pathophysiology. Based on the presynaptic localization of mGluR4 in brain regions involving anxiety and mood disorders, and attenuating excessive brain excitement, mGluR4 activators represent a new generation of anxiolytic therapeutic agents (Eur. J. Pharmacol., 498 (1-3), 153-6, 2004).
Addex在2010年曾報導ADX88178在焦慮之兩種臨床前囓齒動物模型中具活性:在小鼠中之彈珠埋藏測試及在小鼠及大鼠中之EPM。ADX88178亦在口服給藥後在大鼠EPM測試中展現抗焦慮樣譜。 Addex reported in 2010 that ADX88178 was active in two preclinical rodent models of anxiety: marbles burial test in mice and EPM in mice and rats. ADX88178 also exhibited an anxiolytic-like spectrum in rat EPM tests after oral administration.
mGluR4調節劑亦顯示發揮抗抑鬱作用(Neuropharmacology,46(2),151-9,2004)。 mGluR4 modulators have also been shown to exert antidepressant effects ( Neuropharmacology, 46 (2), 151-9, 2004).
此外,mGluR4亦顯示參與胰高血糖素分泌的抑制(Diabetes,53(4),998-1006,2004)。因此,mGluR4之正位或正向異位調節劑經由其降血糖效應具有用於治療2型糖尿病的潛力。 In addition, mGluR4 has also been shown to be involved in the inhibition of glucagon secretion ( Diabetes, 53 (4), 998-1006, 2004) . Therefore, orthotopic or forward ectopic modulators of mGluR4 have the potential for treating type 2 diabetes via their hypoglycemic effect.
此外,mGluR4顯示係在前列腺癌細胞系(Anticancer Res.29(1),371-7,2009)或大腸癌(Cli.Cancer Research,11(9)3288-95,2005)中表現。因此,mGluR4調節劑亦可具有用於治療癌症之潛在作用。 In addition, mGluR4 appears to be expressed in prostate cancer cell lines ( Anticancer Res. 29 (1), 371-7, 2009) or colorectal cancer ( Cli. Cancer Research, 11 (9) 3288-95, 2005) . Therefore, mGluR4 modulators may also have potential effects in the treatment of cancer.
可以預期mGluR4 PAM的其他提出之效應用於治療嘔吐、強迫症及自閉症。 Other proposed effects of mGluR4 PAM can be expected for the treatment of vomiting, obsessive-compulsive disorder, and autism.
式I化合物係以具有寶貴的治療性質為特徵。其可用於治療或預防與mGluR4受體之異位調節劑有關的失調症。 Compounds of formula I are characterized by having valuable therapeutic properties. It can be used to treat or prevent disorders related to ectopic modulators of the mGluR4 receptor.
作為mGluR4受體之異位調節劑之化合物的最佳適應症為帕金森氏病、焦慮、嘔吐、強迫症、自閉症、神經保護、癌症、抑鬱及2型糖尿病。 The best indications for compounds that are ectopic modulators of the mGluR4 receptor are Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, autism, neuroprotection, cancer, depression, and type 2 diabetes.
本發明係關於式I化合物及其醫藥上可接受之鹽,關於此等化合物作為醫藥上活性物質,關於其製造方法及關於在治療或預防與mGluR4受體之異位調節劑有關的失調症(諸如帕金森氏病、焦慮、嘔吐、強迫症、厭食、自閉症、神經保護、癌症、抑鬱及2型糖尿病)中之用途及關於包含式I化合物的醫藥組合物。 The present invention relates to compounds of formula I and their pharmaceutically acceptable salts, to these compounds as pharmaceutically active substances, to their manufacturing methods, and to the treatment or prevention of disorders related to ectopic modulators of the mGluR4 receptor Such as Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, anorexia, autism, neuroprotection, cancer, depression, and type 2 diabetes) and regarding pharmaceutical compositions comprising a compound of formula I.
本發明之另一目標為一種治療或預防帕金森氏病、焦慮、嘔吐、強迫症、自閉症、神經保護、癌症、抑鬱及2型糖尿病之方法,該方法包括投與有效量之式I化合物給有需要之哺乳動物。 Another object of the present invention is a method for treating or preventing Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, autism, neuroprotection, cancer, depression and type 2 diabetes, which method comprises administering an effective amount of formula I The compound is given to a mammal in need.
此外,本發明包括所有外消旋混合物、所有其相應對映異構體及/或光學異構體。 Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and / or optical isomers.
無論所提及的術語係單獨或組合出現,本文使用的一般術語適 用以下定義。 Regardless of whether the mentioned terms appear alone or in combination, the general terms used herein are suitable Use the following definitions.
如本文中所使用,術語「低碳數烷基」表示包含1至7個碳原子之飽和直鏈或分支鏈基團,例如甲基、乙基、丙基、異丙基、正丁基、異丁基、2-丁基、第三丁基及類似。較佳之烷基係具有1至4個碳原子之基團。 As used herein, the term "low-carbon alkyl" means a saturated straight or branched chain group containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, Isobutyl, 2-butyl, third butyl and the like. The preferred alkyl group is a group having 1 to 4 carbon atoms.
術語「經鹵素取代之低碳數烷基」表示如上定義之低碳數烷基,其中至少一個氫原子係經鹵素原子置換。 The term "halogen-substituted lower-carbon alkyl group" means a lower-carbon alkyl group as defined above, wherein at least one hydrogen atom is replaced with a halogen atom.
術語「低碳數烷氧基」表示如上所定義之低碳數烷基,其中該基團係經氧原子連接。 The term "low-carbon alkoxy" means a low-carbon alkyl group as defined above, wherein the group is connected via an oxygen atom.
術語「低碳數伸烷基」表示連接基團,如-CH2-或-CH2CH2-。 The term "low-carbon alkylene" means a linking group such as -CH 2 -or -CH 2 CH 2- .
術語「環烷基」表示含有3至7個碳原子之飽和環,例如環丙基、環丁基、環戊基、環己基或環庚基。 The term "cycloalkyl" means a saturated ring containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
術語「環烷氧基」表示環烷基,其中該基團係經氧原子連接。 The term "cycloalkoxy" means a cycloalkyl group in which the group is attached via an oxygen atom.
術語「鹵素」表示氯、碘、氟及溴。 The term "halogen" means chlorine, iodine, fluorine and bromine.
術語「選自吡啶基、嘧啶基、嗒嗪基、噻唑基、咪唑基、吡唑基或三唑基的5或6-員雜芳基」表示以下基團;
術語「醫藥上可接受的酸加成鹽」涵蓋與諸如以下之無機酸及有機酸之鹽:鹽酸、硝酸、硫酸、磷酸、檸檬酸、甲酸、富馬酸、馬 來酸、乙酸、琥珀酸、酒石酸、甲磺酸、對甲苯磺酸及類似。 The term "pharmaceutically acceptable acid addition salts" encompasses salts with inorganic and organic acids such as: hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, horse Maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
本發明之一實施例係下式Ia化合物,
R1係F或Cl;R2為-(CH2)nO-低碳數烷基、經鹵素取代之低碳數烷基或-(CH2)nC(O)O-低碳數烷基,n為1、2或3;R3為氫、低碳數烷基或-(CH2)nO-低碳數烷基;或其醫藥上可接受的鹽或酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體及/或立體異構體,例如以下化合物:(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-甲氧基乙基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 R 1 is F or Cl; R 2 is-(CH 2 ) n O-lower alkyl, halogen-substituted lower alkyl or-(CH 2 ) n C (O) O-lower alkyl N, 1, 2 or 3; R 3 is hydrogen, a low-carbon alkyl group or-(CH 2 ) n O-low-carbon alkyl group; or a pharmaceutically acceptable salt or acid addition salt thereof, and Racemic mixtures or their corresponding enantiomers and / or optical isomers and / or stereoisomers, such as the following compounds: (9aS) -7- [2,6-difluoro-4- (2-benzene Ethynyl) phenyl] -2- (2-methoxyethyl) -9a-methyl-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6, 8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(3-甲氧基丙基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (3-methoxypropyl) -9a-methyl-4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2,2,2-三氟乙基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮或4-[(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-基]丁酸乙酯。 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2,2,2-trifluoroethyl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione or 4-[(9aS) -7- [2,6-difluoro-4- (2- Phenylethynyl) phenyl] -9a-methyl-1,6,8-trisoxy-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-2-yl] Ethyl butyrate.
本發明之另一目標係下式Ib化合物,
其中 R1係F或Cl;L為低碳數伸烷基;R2為經低碳數烷基或經鹵素取代之苯基;R3為氫、低碳數烷基或-(CH2)nO-低碳數烷基;n為1、2或3;或其醫藥上可接受的鹽或酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體及/或立體異構體,例如以下化合物(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(間-甲苯基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 Wherein R 1 is F or Cl; L is a low-carbon alkylene; R 2 is a phenyl substituted with a low-carbon alkyl or halogen; R 3 is hydrogen, a low-carbon alkyl or-(CH 2 ) n O-lower alkyl; n is 1, 2 or 3; or a pharmaceutically acceptable salt or acid addition salt thereof, a racemic mixture or its corresponding enantiomer and / or optical isomer And / or stereoisomers, such as the following compound (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (m-toluene Methyl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(對-甲苯基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (p-tolylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(鄰-甲苯基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (o-tolylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(2,6-二甲基苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-[(2,6-dimethylphenyl) methyl] -9a-methyl -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-2-[(2-氯苯基)甲基]-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -2-[(2-chlorophenyl) methyl] -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-2-[(3-氯苯基)甲基]-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -2-[(3-chlorophenyl) methyl] -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(2-氟苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-[(2-fluorophenyl) methyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(3-氟苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮或(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(4-氟苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮。 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-[(3-fluorophenyl) methyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione or (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) ) Phenyl] -2-[(4-fluorophenyl) methyl] -9a-methyl-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8 -Triketone.
本發明之另一實施例係下式Ic化合物,
其中R1係氫、F或Cl;L係鍵或低碳數伸烷基;R2為選自吡啶基、嘧啶基、嗒嗪基、噻唑基、咪唑基、吡唑基或三唑基的5或6-員雜芳基,其等視情況經低碳數烷基、鹵素、低碳數烷氧基、=O、苄氧基、環烷氧基、羥基、氰基、經鹵素取代之低碳數烷基、或經-(CH2)nO-低碳數烷基取代;n為1、2或3;R3為氫、低碳數烷基或-(CH2)nO-低碳數烷基;R4為視情況經F取代之苯基;Y為CF或CCl;或其醫藥上可接受的鹽或酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體及/或立體異構體,例如以下化合物:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(3-吡啶基)-3,4,9,9a-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮 Wherein R 1 is hydrogen, F or Cl; L is a bond or a low-carbon alkylene; R 2 is selected from pyridyl, pyrimidinyl, daphrazinyl, thiazolyl, imidazolyl, pyrazolyl, or triazolyl 5 or 6-membered heteroaryl, which are optionally substituted with a lower carbon number alkyl, halogen, lower carbon number alkoxy, = O, benzyloxy, cycloalkoxy, hydroxyl, cyano, halogen substituted Low-carbon alkyl, or substituted with-(CH 2 ) n O-low-carbon alkyl; n is 1, 2 or 3; R 3 is hydrogen, low-carbon alkyl or-(CH 2 ) n O- Low carbon number alkyl; R 4 is phenyl substituted by F as appropriate; Y is CF or CCl; or a pharmaceutically acceptable salt or acid addition salt thereof, a racemic mixture or its corresponding enantiomer And / or optical isomers and / or stereoisomers, such as the following compounds: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- ( 3-pyridyl) -3,4,9,9a-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-嘧啶-4-基-3,4,9,9a-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-pyrimidin-4-yl-3,4,9,9a-tetrahydropyrazino [ 1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-吡啶基)-3,4,9,9a-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-pyridyl) -3,4,9,9a-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基)- 4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl)- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基-2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methyl-2-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基-4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methyl-4-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-(2,6-二氟-4-(苯基乙炔基)苯基)-9a-甲基-2-(4-甲基吡啶-2-基)四氫-1H-吡嗪并[1,2-c]嘧啶-1,6,8(2H,7H)-三酮 (9aRS) -7- (2,6-difluoro-4- (phenylethynyl) phenyl) -9a-methyl-2- (4-methylpyridin-2-yl) tetrahydro-1H-pyridine Azino [1,2-c] pyrimidine-1,6,8 (2H, 7H) -trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methyl-3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methyl-3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methyl-3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(3,5-二甲基-4-吡啶基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (3,5-dimethyl-4-pyridyl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-2-(2-氯-4-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a- 甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -2- (2-chloro-4-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- Methyl-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-2-(2-氯-4-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -2- (2-chloro-4-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-2-(6-氯-3-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -2- (6-chloro-3-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-2-(6-氯-3-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -2- (6-chloro-3-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(6-甲氧基-3-吡啶基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (6-methoxy-3-pyridyl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(6-甲氧基-3-吡啶基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (6-methoxy-3-pyridyl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-6-側氧基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-6-oxo-3-pyridine ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-2-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-5-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-5-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2,6-二甲基嘧啶-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2,6-dimethylpyrimidin-4-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基嘧啶-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrimidin-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基嘧啶- 4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrimidine- 4-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-吡嗪-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-吡嗪-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基吡嗪-2-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methylpyrazin-2-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基嘧啶-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methylpyrimidin-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基嘧啶-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methylpyrimidin-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-甲氧基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-methoxypyrimidin-5-yl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-2-(2-第三丁氧基嘧啶-5-基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -2- (2-Third-butoxypyrimidin-5-yl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS或9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-乙氧基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS or 9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-ethoxypyrimidin-5-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-異丙氧基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-isopropoxypyrimidin-5-yl) -9a-methyl-4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-2-(2-苄氧基嘧啶-5-基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -2- (2-benzyloxypyrimidin-5-yl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-羥基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-hydroxypyrimidin-5-yl) -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-2-[2-(環丙氧基)嘧啶-5-基]-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -2- [2- (cyclopropoxy) pyrimidin-5-yl] -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(5-甲氧基吡嗪-2-基)- 9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (5-methoxypyrazin-2-yl)- 9a-methyl-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-2-(5-苄氧基吡嗪-2-基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -2- (5-benzyloxypyrazin-2-yl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嗒嗪-3-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-3-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-吡嗪-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基嗒嗪-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methylpyrazin-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-6-側氧基-嗒嗪-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-6- pendant oxy-pyridazine- 3-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嗒嗪-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-4-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-6-側氧基-嗒嗪-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-6- pendant oxy-pyridazine- 4-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-噻唑-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-thiazol-2-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基噻唑-2-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methylthiazol-2-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-甲基噻唑-2-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-methylthiazol-2-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
2-[(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-基]噻唑-4-甲腈 2-[(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-1,6,8-trisoxy-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidin-2-yl] thiazole-4-carbonitrile
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[4-(三氟甲基)噻唑-2-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [4- (trifluoromethyl) thiazol-2-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[5-(三氟甲 基)噻唑-2-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [5- (trifluoromethyl ) Thiazol-2-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基咪唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylimidazol-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1,4-二甲基咪唑-2-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1,4-dimethylimidazol-2-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1,2-二甲基咪唑-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1,2-dimethylimidazol-4-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-甲基-1-(2,2,2-三氟乙基)咪唑-4-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2-methyl-1- (2,2,2- Trifluoroethyl) imidazol-4-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2,5-二甲基吡唑-3-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2,5-dimethylpyrazol-3-yl) -9a-methyl -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-4-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-4-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1-乙基吡唑-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1-ethylpyrazol-4-yl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1-異丙基吡唑-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1-isopropylpyrazol-4-yl) -9a-methyl-4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl) -4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[1-(3-甲氧基丙基)吡唑-4-基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- [1- (3-methoxypropyl) pyrazol-4-yl]- 9a-methyl-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-1,2,4-三唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-1,2,4-triazole- 3-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(嘧啶-4-基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (pyrimidin-4-ylmethyl) -4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[(1-甲基吡唑-4-基)甲基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-[(1-methylpyrazol-4-yl) methyl ] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[(2-甲基吡唑-3-基)甲基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-[(2-methylpyrazol-3-yl) methyl ] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-咪唑-1-基乙基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-imidazol-1-ylethyl) -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-(2-甲基咪唑-1-基)乙基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2- (2-methylimidazol-1-yl) ethyl Yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-(2-甲基吡唑-3-基)乙基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2- (2-methylpyrazol-3-yl) Ethyl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-(1-甲基吡唑-4-基)乙基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2- (1-methylpyrazol-4-yl) Ethyl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (1-methylpyrazole-4- ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (1-methylpyrazole-4- ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2- (1-methylpyrazol-4-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aRS)-7-[2-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aRS) -7- [2-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H-pyrazine Benzo [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2- (3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2-嘧啶-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2-pyrimidin-4-yl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮或(9aS)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮。 (9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2- (1-methylpyrazole-4- ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione or (9aS) -7- [2-chloro-4- (2-benzene Ethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-4-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1 , 6,8-trione.
本發明式I化合物之製備可依連續或匯集合成途徑進行。本發明化合物之合成法係顯示於以下反應圖1中。熟習此項技藝者已知進行反應及所得產物純化時所需要的技術。該等方法之以下描述中所使用的取代基及指數具有前文中指定的意義。 The preparation of the compound of formula I according to the present invention can be carried out by a continuous or pooled synthetic route. The synthesis method of the compound of the present invention is shown in the following reaction scheme 1. Those skilled in the art know the techniques required to perform the reaction and to purify the resulting product. The substituents and indices used in the following descriptions of these methods have the meanings specified above.
可藉由下文所給定之方法、藉由實例中所給定之方法或藉由類似方法製造式I化合物。熟習此項技術者已知個別反應步驟之適宜反應條件。反應次序並不限於流程圖中所顯示之次序,然而,依據起始材料及其各別反應性,可自由變更反應步驟之次序。起始材料係可為市售購得或可藉由類似於下文所給定方法之方法、藉由說明或實例中所引用之參考文獻中所述之方法或藉由此項技術中已知之方法進行製備。 Compounds of formula I can be produced by the methods given below, by the methods given in the examples, or by similar methods. Those skilled in the art know the appropriate reaction conditions for the individual reaction steps. The reaction order is not limited to the order shown in the flowchart, however, the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity. The starting materials are commercially available or can be obtained by methods similar to those given below, by methods described in references cited in the description or examples, or by methods known in the art Prepared.
本發明式I化合物及其醫藥上可接受的鹽可藉由此項技術中已知之方法進行製備,例如藉由下文所述之方法變體,該方法包括: The compounds of formula I and their pharmaceutically acceptable salts according to the invention can be prepared by methods known in the art, for example by variants of the methods described below, which methods include:
a)使式IV化合物
與式XLR2化合物反應,其中X為鹵素,
生成式I化合物
且若需要,將該等所得化合物轉化成醫藥上可接受之酸加成鹽。 And, if necessary, the obtained compounds are converted into pharmaceutically acceptable acid addition salts.
式I化合物之製備係進一步更詳細地描述於反應圖1及2及實例1至112中。 The preparation of compounds of formula I is described in more detail in Reaction Figures 1 and 2 and Examples 1 to 112.
通式I之經取代之嘧啶-2,6-二酮化合物可係例如藉由經適宜取代之苯胺或胺基吡啶1與苯基-乙炔2之邵納蓋西拉(Sonogashira)偶合以產生所需式II乙炔基化合物而獲得。使式II乙炔基化合物與式III之經適宜取代之胺基酯或胺基酸與光氣或光氣等效物(諸如三光氣或羰基二咪唑(CDI))在鹼(諸如三乙胺)之存在或不存在下,於溶劑(諸如甲苯或二噁烷)中反應,形成所需通式IV之乙炔基-苯基、乙炔基-吡啶基或乙炔基-嘧啶基取代之咪唑啶-2,4-二酮化合物(反應圖1)。涉及中間產 物II與III反應,形成脲衍生物,然後其與酯基反應以形成式IV之嘧啶二酮之兩個步驟可以在一鍋式兩步反應中進行或該兩個步驟可以依次以正常或反轉順序(醯胺形成,接著脲形成)進行,端視可用起始材料而定。L-R2取代基之引入亦可在合成次序中之各個不同點經由相應中間產物III或IV之官能化而實現。 Substituted pyrimidine-2,6-dione compounds of the general formula I can be produced, for example, by the coupling of a suitably substituted aniline or aminopyridine 1 with Sonogashira of phenyl-acetylene 2 . Obtained from an ethynyl compound of formula II . Ethynyl compound of the formula II and of formula III by the appropriately substituted amine or amino acid ester with phosgene or a phosgene equivalent (such as triphosgene or carbonyl diimidazole (the CDI)) of a base (such as triethylamine) under the presence or absence of a solvent (such as toluene or dioxane) were reacted to form the desired formula IV ethynyl - phenyl, ethynyl - pyridyl or ethynyl - pyrimidinyl substituted imidazole piperidine of -2 , 4-diketone compound (Reaction Figure 1). The two steps involving the reaction of intermediates II with III to form a urea derivative, which then reacts with an ester group to form a pyrimidinedione of formula IV can be performed in a one-pot two-step reaction or the two steps can be sequentially normal Or reverse the order (formamide formation followed by urea formation), depending on the starting materials available. The introduction of LR 2 substituents can also be achieved at various points in the synthetic sequence via the functionalization of the corresponding intermediate products III or IV .
R4取代基亦可藉由使式I化合物與三甲基甲矽烷基乙炔反應,接著在氟化物之存在下與芳基碘或芳基溴R4-X之第二邵納蓋西拉反應,以產生相應的經R4取代之乙炔衍生物II而引入。 The R 4 substituent can also be reacted by reacting a compound of formula I with trimethylsilyl acetylene, followed by a second Shaona Gesila reaction with aryl iodide or aryl bromide R 4 -X in the presence of a fluoride. To introduce the corresponding R 4 substituted acetylene derivative II.
一般而言,用於合成式I化合物之步驟的次序亦可在某些情況下經進一步修改。亦可行的是,在對掌性固定相上分離式I、III或IV化合物之外消旋混合物,以產生相應光學上純的對映異構體。式IV中間產物亦可例如使用以下方法(反應圖2)合成:
在鹼性或酸性條件下,利用醇(2)使經適宜取代之環氧化物(1)開 環,該醇具有連接之保護基部分,諸如烯丙基-醇或桂皮-醇。使所形成之二級醇(3)氧化為相應酮4,然後使用魏悌希或魏悌希-霍納條件轉化為相應α,β-不飽和酯5。然後用氨處理該酯,產生邁克爾加成產物6,使用前文述及之相同條件將其環化,產生化合物8。然後使用適宜經保護之溴乙基胺基衍生物使脲氮烷基化,產生烷基化化合物9。使該醇脫去保護基,接著氧化為羧酸,產生環化產物(10),使其脫去保護基,產生中間產物V,然後使其進一步轉化以形成式I化合物。 Under basic or acidic conditions, a suitably substituted epoxide ( 1 ) is ring-opened with an alcohol ( 2 ) having an attached protecting group moiety, such as allyl-alcohol or cinnamon-alcohol. The secondary alcohol ( 3 ) formed is oxidized to the corresponding ketone 4 and then converted to the corresponding α, β-unsaturated ester 5 using Weinrich or Weinrich-Horner conditions. This ester is then treated with ammonia to produce a Michael addition product 6 which is cyclized using the same conditions described previously to produce compound 8 . The urea nitrogen is then alkylated with a suitably protected bromoethylamine derivative to produce an alkylated compound 9 . The alcohol is deprotected and then oxidized to a carboxylic acid to produce a cyclized product ( 10 ), which is deprotected to produce an intermediate product V , which is then further converted to form a compound of formula I.
生物分析及資料:Biological analysis and data:
使用活體外Ca2+動員分析對在HEK293細胞中表現之重組人類mGlu4測定ECEC determination of recombinant human mGlu4 expressed in HEK293 cells using in vitro Ca2 + mobilization analysis 5050 值:value:
產生經編碼人類mGlu4受體之cDNA穩定轉染之單株HEK-293細胞系;為了讓mGlu4正向異位調節劑(PAM)發揮作用,選拔受體表現水平低且組成性受體活性低之細胞系,以便讓激動活性與PAM活性呈現差異化。根據標準協定(Freshney,2000),將細胞培養於含有高葡萄糖之杜貝卡氏改良依格培養基(Dulbecco’s Modified Eagle Medium)中,該培養基補充有1mM麩胺醯胺、10%(vol/vol)熱滅活小牛血清、盤尼西林(Penicillin)/鏈黴素、50μg/ml潮黴素(hygromycin)及15μg/ml殺稻瘟菌素(blasticidin)(所有細胞培養試劑及抗生素均來自Invitrogen,Basel,Switzerland)。 Generation of a single HEK-293 cell line stably transfected with cDNA encoding human mGlu4 receptor; In order for mGlu4 positive ectopic modulator (PAM) to work, select low-receptor expression levels and low constitutive receptor activity Cell line in order to differentiate agonistic activity from PAM activity. According to standard protocol (Freshney, 2000), cells were cultured in Dulbecco's Modified Eagle Medium containing high glucose, which was supplemented with 1 mM glutamine, 10% (vol / vol) Heat-inactivated calf serum, Penicillin / streptomycin, 50 μg / ml hygromycin and 15 μg / ml blasticidin (all cell culture reagents and antibiotics are from Invitrogen, Basel, Switzerland).
在實驗前約24小時,將5 x 104個細胞/孔接種於經聚-D-離胺酸塗覆之96孔黑底/透明底板中。在37℃下,以含於加樣緩衝液(1 x HBSS,20mM HEPES)中之2.5μM Fluo-4AM處理該等細胞1小時,並以加樣緩衝液清洗五次。將該等細胞轉移至功能性藥物篩選系統(Functional Drug Screening System)7000(Hamamatsu,Paris,France)中,並在37℃下添加11份測試化合物之半對數連續稀釋液,並培育該等細胞10至30分鐘,同時連線記錄螢光。在此預培育步驟後,以相當 於EC20之濃度添加激動劑(2S)-2-胺基-4-膦醯基丁酸(L-AP4)至該等細胞中,同時連線記錄螢光;為說明細胞日與日之間的反應性變化,在即將進行各次實驗前藉由記錄L-AP4之全劑量-反應曲線測定L-AP4之EC20。 Approximately 24 hours before the experiment, 5 x 10 4 cells / well were seeded in a poly-D-lysine-coated 96-well black matrix / clear bottom plate. These cells were treated with 2.5 μM Fluo-4AM in loading buffer (1 x HBSS, 20 mM HEPES) for 1 hour at 37 ° C, and washed five times with loading buffer. The cells were transferred to a Functional Drug Screening System 7000 (Hamamatsu, Paris, France), and 11 semi-log serial dilutions of the test compound were added at 37 ° C, and the cells were incubated 10 Up to 30 minutes while recording fluorescence. After this pre-incubation step, add agonist (2S) -2-amino-4-phosphinofluorenylbutyric acid (L-AP4) to these cells at a concentration equivalent to EC 20 , and record the fluorescence at the same time In order to explain the change in the reactivity between cell days, the EC 20 of L-AP4 was determined by recording the full dose-response curve of L-AP4 immediately before each experiment.
將反應測定為以螢光減去基底(亦即在未添加L-AP4下之螢光)計之峰增加,並針對以L-AP4之飽和濃度所獲得之最大刺激效應標準化。依據最大%刺激,使用XLfit繪製圖表,XLfit為一種使用萊文貝格馬奎特(Levenburg Marquardt)算法迭代地繪製數據之曲線擬合程式。所用之單點競爭分析方程式為y=A+((B-A)/(1+((x/C)D))),其中y為最大%刺激效應,A為最小y值,B為最大y值,C為EC50,x為競爭化合物之濃度之log10,而D為曲線斜率(希爾(Hill)係數)。由此等曲線計算出EC50(達到50%最大受體活化時之藥物濃度)、希爾係數及以L-AP4之飽和濃度所獲得以最大刺激效應的%計之最大反應(參見圖1)。 The response was measured as the peak increase in fluorescence minus the substrate (i.e., fluorescence without the addition of L-AP4) and normalized to the maximum stimulating effect obtained at the saturated concentration of L-AP4. XLfit is used to draw a chart based on the maximum% stimulus. XLfit is a curve fitting program that iteratively draws data using the Levenburg Marquardt algorithm. The single-point competition analysis equation used is y = A + ((BA) / (1 + ((x / C) D))), where y is the maximum% stimulus effect, A is the minimum y value, and B is the maximum y value. C is the EC 50, x is the concentration of competing compound and the log10, and D is the slope (Hill (Hill) coefficient). From these curves, the EC 50 (drug concentration at which 50% of the maximum receptor activation was reached), the Hill coefficient, and the maximum response in% of the maximum stimulating effect obtained with the saturated concentration of L-AP4 (see Figure 1) .
在與PAM測試化合物預培育期間(亦即在施用L-AP4之EC20濃度前)所獲得之正訊號係表示激動劑活性,缺乏此等訊號係顯示缺乏激動劑活性。添加L-AP4之EC20濃度後觀察到訊號之減弱係表示該測試化合物具有抑制活性。 Positive signals obtained during pre-incubation with PAM test compounds (ie, prior to the EC 20 concentration of L-AP4) indicate agonist activity, and the absence of these signals indicates a lack of agonist activity. The decrease in signal observed after the EC 20 concentration of L-AP4 was added indicates that the test compound has inhibitory activity.
圖1:說明mGlu4 PAM Ca2+動員篩選分析之實驗結果及EC50及% Emax值之測定。 Figure 1: Illustrates the experimental results of mGlu4 PAM Ca 2+ mobilization screening analysis and the determination of EC 50 and% E max values.
實例及資料列表:Examples and information list:
式(I)化合物及其醫藥上可接受的鹽可用作(例如)呈醫藥製劑形式之藥劑。該等醫藥製劑可口服投與,例如呈錠劑、包衣錠劑、糖錠、硬及軟明膠膠囊、溶液、乳液或懸浮液之形式。然而,亦可經直腸給藥(例如呈栓劑之形式),或非經腸給藥(例如呈注射溶液之形式)。 Compounds of formula (I) and their pharmaceutically acceptable salts can be used, for example, as medicaments in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of lozenges, coated lozenges, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, it can also be administered rectally (for example in the form of suppositories) or parenterally (for example in the form of an injection solution).
可藉由用於製造醫藥製劑之醫藥上惰性之無機或有機載劑處理該等式(I)化合物及其醫藥上可接受之鹽。可使用乳糖、玉米澱粉或其衍生物、滑石粉、硬脂酸或其鹽等作為(例如)錠劑、包衣錠劑、糖錠及硬明膠膠囊之此等載劑。適用於軟明膠膠囊之載劑為(例如)植物油、蠟、脂肪、半固體及液體多元醇等;然而,依據活性物質之性質,在軟明膠膠囊之情況下,通常無需載劑。適合製造溶液及糖漿之 載劑為(例如)水、多元醇、蔗糖、轉化糖、葡萄糖等。佐劑(例如醇、多元醇、甘油、植物油及類似物)可用於式(I)化合物之水溶性鹽之水性注射溶液,但一般並非必需。適用於栓劑之載劑為(例如)天然油或硬化油、蠟、脂肪、半液體或液體多元醇等。 The compounds of formula (I) and their pharmaceutically acceptable salts can be treated with a pharmaceutically inert inorganic or organic carrier used in the manufacture of pharmaceutical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, and the like can be used as such carriers for lozenges, coated lozenges, dragees, and hard gelatin capsules, for example. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solids, and liquid polyols; however, depending on the nature of the active substance, in the case of soft gelatin capsules, carriers are generally not required. Suitable for making solutions and syrups Carriers are, for example, water, polyols, sucrose, invert sugar, glucose, and the like. Adjuvants (such as alcohols, polyols, glycerol, vegetable oils, and the like) can be used in aqueous injection solutions of water-soluble salts of compounds of formula (I), but are generally not required. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
此外,醫藥製劑可包含保存劑、增溶劑、安定劑、潤濕劑、乳化劑、甜味劑、著色劑、矯味劑、用於改變滲透壓之鹽、緩衝劑、掩蓋劑或抗氧化劑。其等亦可包含其他具治療價值之物質。 In addition, the pharmaceutical preparation may contain a preservative, a solubilizer, a stabilizer, a wetting agent, an emulsifier, a sweetener, a colorant, a flavoring agent, a salt for changing the osmotic pressure, a buffer, a masking agent, or an antioxidant. They may also include other substances of therapeutic value.
如先前所述,包含式(I)化合物或其醫藥上可接受之鹽及治療上惰性賦形劑之藥物,如同一種用於製造該等藥物之方法亦係本發明之一目標,該方法包括使一或多種式I化合物或其醫藥上可接受之鹽及(若需要)一或多種其他治療上有價值之物質與一或多種治療上惰性載劑一起形成蓋倫劑型。 As mentioned previously, a drug comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, as well as a method for manufacturing such drugs, is also an object of the present invention, the method comprising One or more compounds of formula I, or a pharmaceutically acceptable salt thereof, and, if necessary, one or more other therapeutically valuable substances are formed into a galenic dosage form with one or more therapeutically inert carriers.
另外如先前所述,式(I)化合物於製備可用於預防及/或治療上述疾病之藥物之用途亦係本發明之一目標。 In addition, as mentioned previously, the use of a compound of formula (I) in the preparation of a medicament that can be used to prevent and / or treat the aforementioned diseases is also an object of the present invention.
劑量可在寬廣範圍內變化,且理當符合各特定情況之個別要求。一般而言,口服或非經腸投與之有效劑量係介於0.01至20mg/kg/天之間,且就所有所述適應症而言,劑量較佳為0.1至10mg/kg/天。體重70kg之成人的每日劑量相應地處在0.7至1400mg/天之間,較佳在7與700mg/天之間。 Dosages can be varied within a wide range, and should reasonably meet the individual requirements of each particular situation. Generally, the effective dose for oral or parenteral administration is between 0.01 and 20 mg / kg / day, and for all said indications, the dose is preferably between 0.1 and 10 mg / kg / day. The daily dose for an adult weighing 70 kg is correspondingly between 0.7 and 1400 mg / day, preferably between 7 and 700 mg / day.
製備包含本發明化合物之醫藥組合物:Preparation of a pharmaceutical composition comprising a compound of the invention:
以習知方式製備具有以下組成之錠劑: Tablets having the following composition are prepared in a conventional manner:
mg/錠劑mg / tablet
實驗部分:Experimental part:
實例1Example 1
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(3-吡啶基)-3,4,9,9a-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (3-pyridyl) -3,4,9,9a-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:2,6-二氟-4-苯基乙炔基-苯基胺Step 1: 2,6-Difluoro-4-phenylethynyl-phenylamine
將雙-(三苯基膦)-二氯化鈀(II)(826mg,1.18mmol,0.02equiv.)溶解於100ml THF中。在室溫下,添加2,6-二氟-4-碘苯胺(15g,58.8mmol)及苯基乙炔(7.2g,7.8ml,70.6mmol,1.2equiv.)。添加三乙胺(29.8g,41ml,0.29mol,5equiv.)、三苯基膦(617mg,2.35mmol,0.04equiv.)及碘化銅(I)(112mg,0.58mmol,0.01equiv.),並在60℃下攪拌該混合物1小時。使該反應混合物冷卻並用飽和NaHCO3溶液萃取並用乙酸乙酯萃取兩次。用水清洗有機層三次,經硫酸鈉乾燥,並蒸發至乾。藉由急驟層析於矽膠管柱上,用乙酸乙酯:庚烷梯度0:100至40:60洗脫,純化粗製產物。獲得呈黃色固體之所需2,6-二氟-4-苯基乙炔基-苯基胺(12.6g,93%產率),MS:m/e=230.1(M+H+)。 Bis- (triphenylphosphine) -palladium (II) dichloride (826 mg, 1.18 mmol, 0.02 equiv.) Was dissolved in 100 ml of THF. At room temperature, 2,6-difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 equiv.) Were added. Add triethylamine (29.8g, 41ml, 0.29mol, 5equiv.), Triphenylphosphine (617mg, 2.35mmol, 0.04equiv.) And copper (I) iodide (112mg, 0.58mmol, 0.01equiv.), And The mixture was stirred at 60 ° C for 1 hour. The reaction mixture was cooled and extracted twice with saturated NaHCO 3 solution and extracted with ethyl acetate. The organic layer was washed three times with water, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column, eluting with a gradient of ethyl acetate: heptane from 0: 100 to 40:60. The desired 2,6-difluoro-4-phenylethynyl-phenylamine (12.6 g, 93% yield) was obtained as a yellow solid, MS: m / e = 230.1 (M + H + ).
步驟2:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-3,4,9,9a-四氫-2H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮Step 2: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -3,4,9,9a-tetrahydro-2H-pyrazino [1, 2-c] pyrimidine-1,6,8-trione
在6ml密閉容器中引入2,6-二氟-4-苯基乙炔基-苯基胺(實例1步驟1)(100mg,0.44mmol)及甲苯(2.5ml)。在室溫下,添加羰基二咪唑(149mg,0.92mmol,2.1equiv.)。在115℃下攪拌該混合物40分鐘。向該混合物添加2-(3-側氧基哌嗪-2-基)乙酸乙酯[Abelman & al.,Tetrahedron Lett.44,1823(2003)](81mg,0.44mmol,1.0equiv.),並在115℃下攪拌16小時。使該反應混合物冷卻,在真空中濃縮並直接裝載至矽膠管柱上。藉由急驟層析,用10:90至100:0乙酸乙酯:庚烷梯度洗脫,純化粗製產物。獲得呈淺黃色固體之標題化合物(50mg,29%產率),MS:m/e=396.1(M+H+)。 Introducing 2,6-difluoro-4-phenylethynyl-sealed container in 6ml - phenylamine (Step 1 Examples 1) (100mg, 0.44mmol) and toluene (2.5ml). At room temperature, carbonyldiimidazole (149 mg, 0.92 mmol, 2.1 equiv.) Was added. The mixture was stirred at 115 ° C for 40 minutes. To this mixture was added ethyl 2- (3-oxopiperazin-2-yl) acetate [Abelman & al., Tetrahedron Lett. 44, 1823 (2003)] (81 mg, 0.44 mmol, 1.0 equiv.), And Stir at 115 ° C for 16 hours. The reaction mixture was allowed to cool, concentrated in vacuo and loaded directly onto a silica gel column. The crude product was purified by flash chromatography, eluting with a gradient of 10:90 to 100: 0 ethyl acetate: heptane. The title compound was obtained as a pale yellow solid (50 mg, 29% yield), MS: m / e = 396.1 (M + H + ).
步驟3:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(3-吡啶基)-3,4,9,9a-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮Step 3: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (3-pyridyl) -3,4,9,9a-tetrahydro Pyrazino [1,2-c] pyrimidine-1,6,8-trione
將(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-3,4,9,9a-四氫-2H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(70mg,0.177mmol)溶解於二噁烷(2.0ml)中。在室溫下,添加Cs2CO3(115mg,0.354mmol,2.0equiv.)、3-溴吡啶(31mg,0.195mmol,1.1equiv.)、乙酸鈀(II)(8.0mg,0.035mmol,0.2equiv.)及4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃[Xantphos®](30.7mg,0.053mmol,0.3equiv.)。在110℃下攪拌該混合物4小時。蒸發該反應混合物,並直接裝載至矽膠管柱上。藉由急驟層析,用乙酸乙酯:庚烷0:100至100:0梯度洗脫,純化粗製產物。獲得呈白色固體之標題化合物(47mg,56%產率),MS:m/e=473.2(M+H+)。 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -3,4,9,9a-tetrahydro-2H-pyrazino [1,2- c] Pyrimidine-1,6,8-trione (70 mg, 0.177 mmol) was dissolved in dioxane (2.0 ml). At room temperature, Cs 2 CO 3 (115 mg, 0.354 mmol, 2.0 equiv.), 3-bromopyridine (31 mg, 0.195 mmol, 1.1 equiv.), Palladium (II) acetate (8.0 mg, 0.035 mmol, 0.2 equiv) were added. .) And 4,5-bis (diphenylphosphino) -9,9-dimethyldibenzopiperan [Xantphos®] (30.7 mg, 0.053 mmol, 0.3 equiv.). The mixture was stirred at 110 ° C for 4 hours. The reaction mixture was evaporated and loaded directly onto a silica gel column. The crude product was purified by flash chromatography, eluting with a gradient of ethyl acetate: heptane 0: 100 to 100: 0. The title compound was obtained as a white solid (47 mg, 56% yield), MS: m / e = 473.2 (M + H + ).
實例2Example 2
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-嘧啶-4-基-3,4,9,9a-(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-pyrimidin-4-yl-3,4,9,9a- 四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-3,4,9,9a-四氫-2H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例1步驟2)及4-溴嘧啶鹽酸鹽獲得呈白色固體之標題化合物,MS:m/e=474.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -3,4,9,9a -Tetrahydro-2H-pyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 1, step 2) and 4-bromopyrimidine hydrochloride to obtain the title compound as a white solid, MS: m / e = 474.2 (M + H + ).
實例3Example 3
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-吡啶基)-3,4,9,9a-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-pyridyl) -3,4,9,9a-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-3,4,9,9a-四氫-2H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例1步驟2)及2-溴嘧啶獲得呈淺黃色固體之標題化合物,MS:m/e=473.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -3,4,9,9a -Tetrahydro-2H-pyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 1, step 2) and 2-bromopyrimidine to obtain the title compound as a pale yellow solid, MS: m / e = 473.2 (M + H + ).
實例4Example 4
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(4.1):Step 1: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [ 1,2-c] pyrimidine-1,6,8-trione (4.1):
使用類似於實例1步驟2中所述之化學作用,自2,6-二氟-4-苯基乙炔基-苯基胺(實例1步驟1)及2-[(2RS)-2-甲基-3-側氧基-哌嗪-2-基]乙酸甲酯[Abelman & al.,Tetrahedron Lett.44,1823(2003)]獲得呈白色固體之標題化合物,MS:m/e=410.2(M+H+)。 Using chemistry similar to Example 1 described in the step 2, from 2,6-difluoro-4-phenyl ethynyl - phenylamine (Examples 1 Step 1) and 2 - [(2RS) -2- methyl Methyl-3-oxo-piperazin-2-yl] methyl acetate [Abelman & al., Tetrahedron Lett. 44 , 1823 (2003)] to obtain the title compound as a white solid, MS: m / e = 410.2 ( M + H + ).
步驟2:(9aS)-及(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(4.2a及4.2b):Step 2: (9aS)-and (9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetra Hydropyrazino [1,2-c] pyrimidine-1,6,8-trione (4.2a and 4.2b):
藉由對掌性HPLC使用Chiralpak IE管柱使用(己烷/EtOH/DCM/Et2N-70/20/10/0.1%)實現對映異構體之對掌性分離,得到呈灰白色固體之(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(4.2a)(MS:410.1(M+H+));及呈灰白色固體之(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(4.2b)(MS:410.1(M+H+))。 Chiralpak IE column using palladium HPLC (hexane / EtOH / DCM / Et 2 N-70 / 20/10 / 0.1%) was used to achieve the enantiomeric separation of the enantiomers to give an off-white solid. (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2 -c] pyrimidine-1,6,8-trione ( 4.2a ) (MS: 410.1 (M + H + )); and (9aR) -7- [2,6-difluoro-4- as an off-white solid (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( 4.2b ) (MS: 410.1 (M + H + )).
步驟2:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮Step 2: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl) -4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(4.1)(實例4步驟1)及2-溴吡啶獲得呈淺黃色固體之標題化合物,MS:m/e=487.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( 4.1 ) (Example 4 step 1) and 2-bromopyridine to give the title compound as a pale yellow solid , MS: m / e = 487.2 (M + H + ).
實例5Example 5
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
將(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(4.2a)(實例4步驟2)(60mg,0.15mmol)、2-碘吡啶(60.1mg,0.29mmol,2.0equiv.)及K2CO3(40.5mg,0.29mmol,2.0equiv.)與二噁烷(1.8ml)合併,得到棕色懸浮液。在氬氣下超音波處理3分鐘後,添加碘化銅(I)(5.58mg,0.29mmol,0.2equiv.)及反式-N,N’-二甲基環己烷-1,2-二胺(8.34mg,9.27μl,0.59mmol,0.4equiv.)。在氬氣下,在140℃下攪拌反應混合物2h。 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1, 2-c] pyrimidine-trione -1,6,8- (4.2a) (Examples 4, step 2) (60mg, 0.15mmol), 2- iodo-pyridine (60.1mg, 0.29mmol, 2.0equiv.) and K 2 CO 3 (40.5 mg, 0.29 mmol, 2.0 equiv.) Was combined with dioxane (1.8 ml) to give a brown suspension. After 3 minutes of ultrasonic treatment under argon, copper (I) iodide (5.58 mg, 0.29 mmol, 0.2 equiv.) And trans-N, N'-dimethylcyclohexane-1,2-di Amine (8.34 mg, 9.27 μl, 0.59 mmol, 0.4 equiv.). The reaction mixture was stirred at 140 ° C. for 2 h under argon.
將反應混合物在真空中濃縮並吸附在胺基相矽膠上。藉由在20g矽膠上之急驟層析,用20%至100% EtOAc/庚烷梯度洗脫,純化粗物質。獲得呈白色固體之標題化合物(46mg,65%產率),MS:m/e=487.3(M+H+)。 The reaction mixture was concentrated in vacuo and adsorbed on an amine phase silicone. The crude material was purified by flash chromatography on 20 g of silica, eluting with a gradient of 20% to 100% EtOAc / heptane. The title compound was obtained as a white solid (46 mg, 65% yield), MS: m / e = 487.3 (M + H + ).
實例6Example 6
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-溴吡啶獲得呈灰白色固體之標題化合物,MS:m/e=487.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 3-bromopyridine to give the title compound as an off-white solid, MS: m / e = 487.2 (M + H + ).
實例7Example 7
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及3-碘吡啶獲得呈灰白色固體之標題化合物,MS:m/e=487.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 3-iodopyridine to give the title compound as an off-white solid, MS: m / e = 487.3 (M + H + ).
實例8Example 8
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-溴吡啶獲得呈灰白色固體之標題化合物,MS:m/e=487.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 4-bromopyridine to give the title compound as an off-white solid, MS: m /e=487.2(M+H + ).
實例9Example 9
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-碘吡啶獲得呈白色固體之標題化合物,MS:m/e=487.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-iodopyridine to give the title compound as a white solid, MS: m / e = 487.3 (M + H + ).
實例10Example 10
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基-2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methyl-2-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴-6-甲基吡啶獲得呈白色固體之標題化合物,MS:m/e=501.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromo-6-methylpyridine to obtain the title as a white solid Compound, MS: m / e = 501.2 (M + H + ).
實例11Example 11
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基-4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methyl-4-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-溴-2-甲基吡啶獲得呈淺黃色固體之標題化合物,MS:m/e=501.3(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 4-bromo-2-methylpyridine were obtained as a pale yellow solid Title compound, MS: m / e = 501.3 (M + H + ).
實例12Example 12
(9aRS)-7-(2,6-二氟-4-(苯基乙炔基)苯基)-9a-甲基-2-(4-甲基吡啶-2-基)四氫-1H-吡嗪并[1,2-c]嘧啶-1,6,8(2H,7H)-三酮(9aRS) -7- (2,6-difluoro-4- (phenylethynyl) phenyl) -9a-methyl-2- (4-methylpyridin-2-yl) tetrahydro-1H-pyridine Azino [1,2-c] pyrimidine-1,6,8 (2H, 7H) -trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶- 1,6,8-三酮(實例4步驟1)及2-溴-4-甲基吡啶獲得呈白色固體之標題化合物,MS:m/e=501.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromo-4-methylpyridine to give the title as a white solid Compound, MS: m / e = 501.2 (M + H + ).
實例13Example 13
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及2-溴-4-甲基吡啶獲得呈白色固體之標題化合物,MS:m/e=501.3(M+H+)。 Using a chemical action similar to that described in Example 3, step 3, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 2-bromo-4-methylpyridine to give the title as a white solid Compound, MS: m / e = 501.3 (M + H + ).
實例14Example 14
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methyl-3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-溴-5-甲基吡啶獲得呈白色固體之標題化合物,MS:m/e=501.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 3-bromo-5-methylpyridine to give the title as a white solid Compound, MS: m / e = 501.2 (M + H + ).
實例15Example 15
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methyl-3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-溴-5-甲基吡啶獲得呈灰白色固體之標題化合物,MS:m/e=501.2(M+H+)。 Using a chemical action similar to that described in Example 3, step 3, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 3-bromo-5-methylpyridine to give the title as an off-white solid Compound, MS: m / e = 501.2 (M + H + ).
實例16Example 16
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methyl-3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及5-溴-2-甲基吡啶獲得呈白色結晶固體之標題化合物,MS:m/e=501.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 5-bromo-2-methylpyridine to give the title compound as a white crystalline solid , MS: m / e = 501.3 (M + H + ).
實例17Example 17
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(3,5-二甲基-4-吡啶基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (3,5-dimethyl-4-pyridyl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-溴-3,5-二甲基吡啶鹽酸鹽獲得呈淺黃色固體之標題化合物,MS:m/e=515.2(M+H+)。 Using a chemical action similar to that described in Example 3, step 3, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-bromo-3,5-dimethylpyridine hydrochloride The title compound was obtained as a pale yellow solid, MS: m / e = 515.2 (M + H + ).
實例18Example 18
(9aRS)-2-(2-氯-4-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -2- (2-chloro-4-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-氯-4-碘吡啶獲得呈白色固體之標題化合物,MS:m/e=521.2,523.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-chloro-4-iodopyridine to give the title compound as a white solid , MS: m / e = 521.2, 523.2 (M + H + ).
實例19Example 19
(9aS)-2-(2-氯-4-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -2- (2-chloro-4-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及2-氯-4-碘吡啶獲得呈白色固體之標題化合物,MS:m/e=521.2,523.2(M+H+)。 Using a chemical action similar to that described in Example 3, step 3, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 2-chloro-4-iodopyridine to give the title compound as a white solid , MS: m / e = 521.2, 523.2 (M + H + ).
實例20Example 20
(9aRS)-2-(6-氯-3-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -2- (6-chloro-3-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (實例4步驟1)及2-氯-5-碘吡啶獲得呈結晶淺黃色結晶固體之標題化合物,MS:m/e=521.2,523.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-chloro-5-iodopyridine to obtain the title of crystalline light yellow crystalline solid Compound, MS: m / e = 521.2, 523.2 (M + H + ).
實例21Example 21
(9aS)-2-(6-氯-3-吡啶基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -2- (6-chloro-3-pyridyl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及2-氯-5-碘吡啶獲得呈結晶淺黃色結晶固體之標題化合物,MS:m/e=521.2,523.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 2-chloro-5-iodopyridine to obtain the title of crystalline light yellow crystalline solid Compound, MS: m / e = 521.2, 523.2 (M + H + ).
實例22Example 22
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(6-甲氧基-3-吡啶基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (6-methoxy-3-pyridyl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及5-碘-2-甲氧基吡啶獲得呈白色結晶固體之標題化合物,MS:m/e=517.4(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 5-iodo-2-methoxypyridine to give the title as a white crystalline solid Compound, MS: m / e = 517.4 (M + H + ).
實例23Example 23
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(6-甲氧基-3-吡啶基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (6-methoxy-3-pyridyl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-碘-2-甲氧基吡啶獲得呈白色結晶固體之標題化合物,MS:m/e=517.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-iodo-2-methoxypyridine to give the title as a white crystalline solid Compound, MS: m / e = 517.3 (M + H + ).
實例24Example 24
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-6-側氧基-3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-6-oxo-3-pyridine ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-溴-1-甲基吡啶-2(1H)-酮獲得呈白色結晶固體之標題化合物,MS:m/e=517.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, Obtained from 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-bromo-1-methylpyridine-2 (1H) -one The title compound as a white crystalline solid, MS: m / e = 517.3 (M + H + ).
實例25Example 25
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-2-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴嘧啶獲得呈淺黃色固體之標題化合物,MS:m/e=488.1(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 1 ) and 2-bromopyrimidine to obtain the title compound as a pale yellow solid, MS: m / e = 488.1 (M + H + ).
實例26Example 26
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-溴嘧啶鹽酸鹽獲得呈白色固體之標題化合物,MS:m/e=488.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 4-bromopyrimidine hydrochloride to give the title compound as a white solid, MS: m / e = 488.2 (M + H + ).
實例27Example 27
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-溴嘧啶鹽酸鹽獲得呈白色結晶固體之標題化合物,MS:m/e=488.3(M+H+)。 Using a chemical action similar to that described in Example 3, step 3, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-bromopyrimidine hydrochloride to obtain the title compound as a white crystalline solid , MS: m / e = 488.3 (M + H + ).
實例28Example 28
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嘧啶-5-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrimidin-5-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及5-溴嘧啶獲得呈白色固體之標題化合物,MS:m/e=488.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 5-bromopyrimidine to obtain the title compound as a white solid, MS: m /e=488.2(M+H + ).
實例29Example 29
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2,6-二甲基嘧啶-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2,6-dimethylpyrimidin-4-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-溴-2,6-二甲基嘧啶獲得呈淺黃色固體之標題化合物,MS:m/e=516.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 4-bromo-2,6-dimethylpyrimidine were obtained The title compound as a yellow solid, MS: m / e = 516.2 (M + H + ).
實例30Example 30
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基嘧啶-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrimidin-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-溴-2-甲基嘧啶獲得呈白色固體之標題化合物,MS:m/e=502.4(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 4-bromo-2-methylpyrimidine to obtain the title as a white solid Compound, MS: m / e = 502.4 (M + H + ).
實例31Example 31
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基嘧啶-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrimidin-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-溴-2-甲基嘧啶獲得呈白色固體之標題化合物, MS:m/e=502.3(M+H+)。 Using a chemical action similar to that described in Example 3, step 3, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-bromo-2-methylpyrimidine to obtain the title as a white solid Compound, MS: m / e = 502.3 (M + H + ).
實例32Example 32
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-吡嗪-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴吡嗪獲得呈白色結晶固體之標題化合物,MS:m/e=488.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromopyrazine to obtain the title compound as a white crystalline solid, MS : M / e = 488.2 (M + H + ).
實例33Example 33
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-吡嗪-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及2-溴吡嗪獲得呈白色固體之標題化合物,MS:m/e=488.4(M+H+)。 Using a chemical action similar to that described in Example 3, step 3, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 2-bromopyrazine to obtain the title compound as a white solid, MS: m / e = 488.4 (M + H + ).
實例34Example 34
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基吡嗪-2-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methylpyrazin-2-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二 氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴吡嗪獲得呈白色結晶固體之標題化合物,MS:m/e=502.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromopyrazine to obtain the title compound as a white crystalline solid, MS : M / e = 502.2 (M + H + ).
實例35Example 35
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基嘧啶-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methylpyrimidin-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-溴-6-甲基嘧啶獲得呈白色固體之標題化合物,MS:m/e=502.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-bromo-6-methylpyrimidine to obtain the title compound as a white solid, MS: m / e = 502.2 (M + H + ).
實例36Example 36
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基嘧啶-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methylpyrimidin-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-溴-6-甲基嘧啶獲得呈白色固體之標題化合物,MS:m/e=502.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-bromo-6-methylpyrimidine to obtain the title compound as a white solid, MS: m / e = 502.3 (M + H + ).
實例37Example 37
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-甲氧基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-methoxypyrimidin-5-yl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-溴-2-甲氧基嘧啶獲得呈淺黃色固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-bromo-2-methoxypyrimidine to obtain the title as a pale yellow solid Compound, MS: m / e = 518.3 (M + H + ).
實例38Example 38
(9aS)-2-(2-第三丁氧基嘧啶-5-基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -2- (2-Third-butoxypyrimidin-5-yl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-溴-2-(第三丁氧基)嘧啶獲得呈白色固體之標題化合物,MS:m/e=504.3([m-tBu]+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-bromo-2- (third butoxy) pyrimidine were obtained as white The title compound as a solid, MS: m / e = 504.3 ([m-tBu] +).
實例39Example 39
(9aS或9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-乙氧基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS or 9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-ethoxypyrimidin-5-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-溴-2-乙氧基嘧啶獲得呈白色固體之標題化合物,MS:m/e=532.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-bromo-2-ethoxypyrimidine to obtain the title compound as a white solid , MS: m / e = 532.3 (M + H + ).
實例40Example 40
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-異丙氧基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-isopropoxypyrimidin-5-yl) -9a-methyl-4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-溴-2-異丙氧基嘧啶獲得呈淺黃色固體之標題化合物,MS:m/e=546.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-bromo-2-isopropoxypyrimidine were obtained as a pale yellow solid Title compound, MS: m / e = 546.3 (M + H + ).
實例41Example 41
(9aS)-2-(2-苄氧基嘧啶-5-基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -2- (2-benzyloxypyrimidin-5-yl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及2-(苄氧基)-5-溴嘧啶獲得呈淺黃色固體之標題化合物,MS:m/e=594.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 2- (benzyloxy) -5-bromopyrimidine were obtained as a pale yellow solid Title compound, MS: m / e = 594.3 (M + H + ).
實例42Example 42
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-羥基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-hydroxypyrimidin-5-yl) -9a-methyl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
將(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-甲氧基嘧啶-5-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例36)(60mg,0.116mmol)溶解於氯仿(3.0ml)中。歷時5分鐘之時間添加0.139ml(0.139mmol,1.2eq.)之1M三溴化硼的二氯甲烷溶液含於0.5ml氯 仿中之溶液。在室溫下攪拌該混合物3.5h,然後藉由添加5% NaHCO3溶液(0.6ml)淬滅。用30ml乙酸乙酯稀釋該反應混合物並蒸發。重複該操作兩次。藉由急驟層析,用乙酸乙酯:庚烷50:50至100:0梯度洗脫,然後用MeOH:乙酸乙酯6:94洗脫,再用MeOH:二氯甲烷15:85洗脫,來純化粗產物。獲得呈淺黃色固體之標題化合物(19mg,33%產率),MS:m/e=504.2(M+H+)。 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-methoxypyrimidin-5-yl) -9a-methyl-4 , 9-dihydro -3H- pyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 36) (60mg, 0.116mmol) was dissolved in chloroform (3.0 ml of) the. A solution of 0.139 ml (0.139 mmol, 1.2 eq.) Of 1M boron tribromide in dichloromethane in 0.5 ml of chloroform was added over 5 minutes. The mixture was stirred for 3.5h at room temperature, and then by adding 5% NaHCO 3 solution (0.6 ml of) quenched. The reaction mixture was diluted with 30 ml of ethyl acetate and evaporated. Repeat this operation twice. By flash chromatography, eluting with a gradient of ethyl acetate: heptane 50:50 to 100: 0, then eluting with MeOH: ethyl acetate 6:94 and then with MeOH: dichloromethane 15:85, To purify the crude product. The title compound was obtained as a pale yellow solid (19 mg, 33% yield), MS: m / e = 504.2 (M + H + ).
實例43Example 43
(9aS)-2-[2-(環丙氧基)嘧啶-5-基]-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -2- [2- (cyclopropoxy) pyrimidin-5-yl] -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-溴-2-環丙氧基嘧啶獲得呈白色固體之標題化合物,MS:m/e=544.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-bromo-2-cyclopropoxypyrimidine to obtain the title as a white solid Compound, MS: m / e = 544.2 (M + H + ).
實例44Example 44
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(5-甲氧基吡嗪-2-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (5-methoxypyrazin-2-yl) -9a-methyl-4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及2-溴-5-甲氧基吡嗪獲得呈淺黃色結晶固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 2-bromo-5-methoxypyrazine to give a pale yellow crystalline solid Title compound, MS: m / e = 518.3 (M + H + ).
實例45Example 45
(9aS)-2-(5-苄氧基吡嗪-2-基)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -2- (5-benzyloxypyrazin-2-yl) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及2-(苄氧基)-5-溴吡嗪獲得呈淺黃色固體之標題化合物,MS:m/e=594.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 2- (benzyloxy) -5-bromopyrazine were obtained as pale yellow The title compound as a solid, MS: m / e = 594.3 (M + H + ).
實例46Example 46
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嗒嗪-3-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-3-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-碘嗒嗪獲得呈淺黃色結晶固體之標題化合物,MS:m/e=488.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 3-iodazine to give the title compound as a pale yellow crystalline solid, MS: m / e = 488.3 (M + H + ).
實例47Example 47
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-吡嗪-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及3-碘嗒嗪獲得呈灰白色固體之標題化合物,MS:m/e =488.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 3-iodazine to give the title compound as an off-white solid, MS: m / e = 488.3 (M + H + ).
實例48Example 48
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(6-甲基嗒嗪-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (6-methylpyrazin-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-碘-6-甲基嗒嗪獲得呈白色固體之標題化合物,MS:m/e=502.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 3-iodo-6-methylpyridazine were obtained as a white solid Title compound, MS: m / e = 502.2 (M + H + ).
實例49Example 49
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-6-側氧基-嗒嗪-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-6- pendant oxy-pyridazine- 3-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及6-溴-2-甲基嗒嗪-3(2H)-酮(CAS:1123169-25-4)獲得呈淺黃色結晶固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 6-bromo-2-methylpyrazine-3 (2H) -one (CAS: 1123169-25-4) The title compound was obtained as a pale yellow crystalline solid, MS: m / e = 518.3 (M + H + ).
實例50Example 50
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-嗒嗪-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-pyrazin-4-yl-4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (實例4步驟2)及4-溴嗒嗪氫溴酸鹽獲得呈黃色固體之標題化合物,MS:m/e=488.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-bromopyrazine hydrobromide to obtain the title compound as a yellow solid, MS: m / e = 488.2 (M + H + ).
實例51Example 51
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-6-側氧基-嗒嗪-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-6- pendant oxy-pyridazine- 4-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及5-碘-2-甲基嗒嗪-3(2H)-酮(CAS:153239-91-9)獲得呈淺紅色固體之標題化合物,MS:m/e=518.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (example 4 step 1) and 5-iodo-2-methylpyrazine-3 (2H) -Ketone (CAS: 153239-91-9) to give the title compound as a pale red solid, MS: m / e = 518.2 (M + H + ).
實例52Example 52
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-噻唑-2-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-thiazol-2-yl-4,9-dihydro-3H- Pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴噻唑獲得呈淺黃色結晶固體之標題化合物,MS:m/e=493.1(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromothiazole to give the title compound as a pale yellow crystalline solid, MS : M / e = 493.1 (M + H + ).
實例53Example 53
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(5-甲基噻唑-2-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (5-methylthiazol-2-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴-5-甲基噻唑獲得呈白色固體之標題化合物,MS:m/e=507.1(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromo-5-methylthiazole to obtain the title as a white solid Compound, MS: m / e = 507.1 (M + H + ).
實例54Example 54
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-甲基噻唑-2-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-methylthiazol-2-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴-4-甲基噻唑獲得呈黃色固體之標題化合物,MS:m/e=507.1(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromo-4-methylthiazole to obtain the title as a yellow solid Compound, MS: m / e = 507.1 (M + H + ).
實例55Example 55
2-[(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-基]噻唑-4-甲腈2-[(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-1,6,8-trisoxy-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidin-2-yl] thiazole-4-carbonitrile
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴噻唑-4-甲腈獲得呈淺黃色固體之標題化合物,MS:m/e=518.1(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromothiazole-4-carbonitrile to obtain a light yellow solid Title compound, MS: m / e = 518.1 (M + H + ).
實例56Example 56
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[4-(三氟甲基)噻唑-2-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [4- (trifluoromethyl) thiazol-2-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴-4-(三氟甲基)噻唑獲得呈黃色固體之標題化合物,MS:m/e=561.1(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromo-4- (trifluoromethyl) thiazole were obtained. The title compound as a yellow solid, MS: m / e = 561.1 (M + H + ).
實例57Example 57
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[5-(三氟甲基)噻唑-2-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [5- (trifluoromethyl) thiazol-2-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴-5-(三氟甲基)噻唑獲得呈淺黃色固體之標題化合物,MS:m/e=561.1(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2, 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromo-5- (trifluoromethyl) thiazole were obtained. The title compound as a pale yellow solid, MS: m / e = 561.1 (M + H + ).
實例58Example 58
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基咪唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylimidazol-4-yl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-溴-1-甲基-1H-咪唑獲得呈淺黃色固體之標題化合物,MS:m/e=490.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 4-bromo-1-methyl-1H-imidazole were obtained as a pale yellow solid The title compound, MS: m / e = 490.2 (M + H + ).
實例59Example 59
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1,4-二甲基咪唑-2-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1,4-dimethylimidazol-2-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-溴-1,4-二甲基-1H-咪唑獲得呈淺黃色固體之標題化合物,MS:m/e=504.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 2-bromo-1,4-dimethyl-1H-imidazole were obtained. The title compound as a pale yellow solid, MS: m / e = 504.2 (M + H + ).
實例60Example 60
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1,2-二甲基咪唑-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1,2-dimethylimidazol-4-yl) -9a-methyl- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-溴-1,2-二甲基-1H-咪唑獲得呈淺黃色固體之標題化合物,MS:m/e=504.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 4-bromo-1,2-dimethyl-1H-imidazole were obtained. The title compound as a pale yellow solid, MS: m / e = 504.2 (M + H + ).
實例61Example 61
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-甲基-1-(2,2,2-三氟乙基)咪唑-4-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2-methyl-1- (2,2,2- Trifluoroethyl) imidazol-4-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (實例4步驟2)及4-碘-2-甲基-1-(2,2,2-三氟乙基)-1H-咪唑獲得呈白色固體之標題化合物,MS:m/e=572.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (example 4 step 2) and 4-iodo-2-methyl-1- (2,2,2 -Trifluoroethyl) -1H-imidazole to give the title compound as a white solid, MS: m / e = 572.2 (M + H + ).
實例62Example 62
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-溴-1-甲基-1H-吡唑獲得呈白色固體之標題化合物,MS:m/e=490.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 3-bromo-1-methyl-1H-pyrazole were obtained as a white solid The title compound, MS: m / e = 490.2 (M + H + ).
實例63Example 63
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及3-溴-1-甲基-1H-吡唑獲得呈白色固體之標題化合物,MS:m/e=490.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 3-bromo-1-methyl-1H-pyrazole as a white solid The title compound, MS: m / e = 490.2 (M + H + ).
實例64Example 64
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及5-碘-1-甲基-1H-吡唑獲得呈白色結晶固體之標題化合物,MS:m/e=490.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 5-iodo-1-methyl-1H-pyrazole were obtained as white crystals The title compound as a solid, MS: m / e = 490.2 (M + H + ).
實例65Example 65
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-甲基吡唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-methylpyrazol-3-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-碘-1-甲基-1H-吡唑獲得呈白色結晶固體之標題化合物,MS:m/e=490.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 5-iodo-1-methyl-1H-pyrazole were obtained as white crystals The title compound as a solid, MS: m / e = 490.2 (M + H + ).
實例66Example 66
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2,5-二甲基吡唑-3-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2,5-dimethylpyrazol-3-yl) -9a-methyl -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及5-溴-1,3-二甲基-1H-吡唑獲得呈白色固體之標題化合物,MS:m/e=504.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, Obtained from 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 5-bromo-1,3-dimethyl-1H-pyrazole The title compound as a white solid, MS: m / e = 504.2 (M + H + ).
實例67Example 67
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-4-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-溴-1-甲基-1H-吡唑獲得呈淺黃色固體之標題化合物,MS:m/e=490.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 1) and 3-bromo-1-methyl-1H-pyrazole were obtained as pale yellow The title compound as a solid, MS: m / e = 490.2 (M + H + ).
實例68Example 68
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-4-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及3-溴-1-甲基-1H-吡唑獲得呈白色結晶固體之標題化合物,MS:m/e=490.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 2, step 2) and 3-bromo-1-methyl-1H-pyrazole were obtained as white crystals The title compound as a solid, MS: m / e = 490.3 (M + H + ).
實例69Example 69
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1-乙基吡唑-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1-ethylpyrazol-4-yl) -9a-methyl-4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及1-乙基-4-碘-1H-吡唑獲得呈白色結晶固體之標題化合物,MS:m/e=504.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 1-ethyl-4-iodo-1H-pyrazole were obtained as white crystals The title compound as a solid, MS: m / e = 504.3 (M + H + ).
實例70Example 70
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(1-異丙基吡唑-4-基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (1-isopropylpyrazol-4-yl) -9a-methyl-4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及1-異丙基-4-碘-1H-吡唑獲得呈白色結晶固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (example 4 step 2) and 1-isopropyl-4-iodo-1H-pyrazole were obtained as white The title compound as a crystalline solid, MS: m / e = 518.3 (M + H + ).
實例71Example 71
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl) -4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[1-(2-三甲基甲矽烷基乙氧基甲基)吡唑-4-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 1: (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [1- (2-trimethylsilyl) Ethoxymethyl) pyrazol-4-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione:
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-碘-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡唑(CAS:[220299-49-0])獲得呈白色固體之標題化合物。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 4-iodo-1-((2- (trimethylsilyl) ) Ethoxy) methyl) -1H-pyrazole (CAS: [220299-49-0]) to give the title compound as a white solid.
步驟2:(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 2: (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl) -4 , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione:
向(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[1-(2-三甲 基甲矽烷基乙氧基甲基)吡唑-4-基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(85mg,0.140mmol)含於2ml二噁烷中之經充分攪拌之溶液添加0.35ml(1.4mmol,10eq.)之4M HCl的二噁烷溶液。在55℃下攪拌該反應4h且在室溫下攪拌16h。藉由添加25%氫氧化銨溶液(0.48ml,3.08mmol,22eq.),將該溶液調整至>8並在真空中濃縮。使殘餘物溶於乙酸乙酯中。用水清洗有機相,並在真空中濃縮。藉由在SiO2(20g)上之急驟層析,先後使用50:50至0:100庚烷-乙酸乙酯梯度、4% MeOH/乙酸乙酯作為洗脫劑來純化粗物質。獲得呈白色固體之標題化合物(43mg,64%產率),MS:m/e=476.2(M+H+)。 (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [1- (2-trimethylsilylethoxy) Methyl) pyrazol-4-yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione (85 mg, 0.140 mmol) in 2 ml The well-stirred solution in dioxane was added with 0.35 ml (1.4 mmol, 10 eq.) Of 4M HCl in dioxane. The reaction was stirred at 55 ° C. for 4 h and at room temperature for 16 h. The solution was adjusted to> 8 by adding a 25% ammonium hydroxide solution (0.48 ml, 3.08 mmol, 22 eq.) And concentrated in vacuo. The residue was dissolved in ethyl acetate. The organic phase was washed with water and concentrated in vacuo. By flash chromatography on in the SiO 2 (20g), using successively 50:50 to 0: 100 heptane - ethyl acetate gradient, 4% MeOH / ethyl acetate The crude material was purified as eluent. The title compound was obtained as a white solid (43 mg, 64% yield), MS: m / e = 476.2 (M + H + ).
實例72Example 72
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[1-(3-甲氧基丙基)吡唑-4-基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- [1- (3-methoxypropyl) pyrazol-4-yl]- 9a-methyl-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
在0℃下,向(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(36mg,0.076mmol)含於DMF(2ml)中之溶液添加60%氫化鈉之礦物油懸浮液(3.9mg,0.1mmol,1.3eq.)。攪拌該反應5min並添加1-溴-3-甲氧基丙烷(12.7mg,9.3μl,0.083mmol,1.1eq.)。將黃色溶液升溫至室溫並攪拌2h。用水淬滅該反應混合物。在用乙酸乙酯/水之標準處理後,經MgSO4乾燥有機層,並在真空中濃縮。藉由急驟層析(SiO2(20g)),使用50%至100%乙酸乙酯/庚烷梯度來純化粗物質。獲得呈灰白色固體之標題化合物(16mg,39%產率),MS:m/e=548.2(M+H+)。 To (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl at 0 ° C ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione (36 mg, 0.076 mmol) in DMF (2 ml) was added with 60% hydrogenation Suspension of sodium in mineral oil (3.9 mg, 0.1 mmol, 1.3 eq.). The reaction was stirred for 5 min and 1-bromo-3-methoxypropane (12.7 mg, 9.3 μl, 0.083 mmol, 1.1 eq.) Was added. The yellow solution was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water. After the treatment with ethyl acetate / water standard, the organic layer was dried over MgSO 4, and concentrated in vacuo. By flash chromatography (SiO 2 (20g)), the crude material was purified using 50-100% ethyl acetate / heptane gradient. The title compound was obtained as an off-white solid (16 mg, 39% yield), MS: m / e = 548.2 (M + H + ).
實例73Example 73
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基-1,2,4-三唑-3-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methyl-1,2,4-triazole- 3-yl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及3-碘-1-甲基-1H-1,2,4-三唑獲得呈白色結晶固體之標題化合物,MS:m/e=491.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 3-iodo-1-methyl-1H-1,2,4- Triazole gave the title compound as a white crystalline solid, MS: m / e = 491.2 (M + H + ).
實例74Example 74
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:2-氯-6-氟-4-苯基乙炔基-苯基胺Step 1: 2-Chloro-6-fluoro-4-phenylethynyl-phenylamine
使用類似於實例1步驟1中所述之化學作用,自2-氯-6-氟-4-碘苯胺及苯基乙炔獲得呈橙色固體之標題化合物,MS:m/e=246.1,248.1(M+H+)。 The title compound was obtained as an orange solid from 2-chloro-6-fluoro-4-iodoaniline and phenylacetylene using a chemical reaction similar to that described in Step 1 of Example 1, MS: m / e = 246.1, 248.1 (M + H + ).
步驟2:(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 2: (9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例1步驟2中所述之化學作用,自2-氯-6-氟-4-苯基乙炔基-苯基胺(實例73步驟1)及2-[(2RS)-2-甲基-3-側氧基-哌嗪-2-基] 乙酸甲酯獲得呈白色固體之標題化合物,MS:m/e=424.3,426.2(M+H+)。 Using a chemical reaction similar to that described in Example 2, Step 2 from 2-chloro-6-fluoro-4-phenylethynyl-phenylamine (Example 73, Step 1) and 2-[(2RS) -2-methyl Methyl-3- pendant oxy-piperazin-2-yl] acetate to give the title compound as a white solid, MS: m / e = 424.3, 426.2 (M + H + ).
步驟3:(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 3: (9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例73步驟2)及3-碘吡啶獲得呈淺黃色固體之標題化合物,MS:m/e=503.2,505.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3 , 4,9-tetrahydro-pyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 73 step 2) and 3-iodo-pyridine the title compound as a pale yellow solid, MS: m / e = 503.2, 505.2 (M + H + ).
實例75Example 75
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例73步驟2)及4-碘吡啶獲得呈淺棕色固體之標題化合物,MS:m/e=503.2,505.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3 , 4,9-tetrahydro-pyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 73 step 2) and 4-iodo-pyridine as a pale brown solid of the title compound, MS: m / e = 503.2, 505.2 (M + H + ).
實例76Example 76
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例73步驟2)及2-碘吡啶獲得呈白色固體之標題化合物,MS:m/e =503.2,505.1(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3 , 4,9-tetrahydro-pyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 73 step 2) and 2-iodopyridine was obtained as a white solid of the title compound, MS: m / e = 503.2, 505.1 (M + H + ).
實例77Example 77
(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2-Chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例73步驟2)及4-碘-1-甲基-1H-吡唑獲得呈灰白色固體之標題化合物,MS:m/e=506.2,508.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3 , 4,9-tetrahydro-pyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 73 step 2) and 4-iodo-1-methyl -1H- pyrazole was obtained The title compound as an off-white solid, MS: m / e = 506.2, 508.2 (M + H + ).
實例78Example 78
(9aS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用如實例4步驟2中所述之類似分離技術,藉由對掌性HPLC,使用Chiralpak AD管柱,使用(庚烷/EtOH/NH4OAc-60/39.9/0.1%)作為洗脫劑,實現對映異構體之對掌性分離,得到呈淺棕色固體之(9aS)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(穩定滯轉異構體之1:1混合物),MS:m/e=506.3,508.2(M+H+);以及呈淺棕色固體之(9aR)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(1種穩定滯轉異構體=實體A)(MS:506.2,508.2(M+H+));及呈淺棕色固體之(9aR)-7-[2-氯-6-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8- 三酮(1種穩定滯轉異構體=實體B)(MS:506.2,508.1(M+H+))。 Using a similar separation technique as described in step 2 of Example 4, using chiralpak AD column with palm HPLC using (heptane / EtOH / NH 4 OAc-60 / 39.9 / 0.1%) as the eluent, Enantiomeric separation of the enantiomers was achieved to give (9aS) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl as a light brown solid 2- (4-pyridyl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione (1 of the stable delayed isomers: 1 mixture), MS: m / e = 506.3, 508.2 (M + H + ); and (9aR) -7- [2-chloro-6-fluoro-4- (2-phenylethynyl) as a light brown solid ) Phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione (1 Stable isomers = Entity A) (MS: 506.2, 508.2 (M + H + )); and (9aR) -7- [2-chloro-6-fluoro-4- (2) as a light brown solid -Phenylethynyl) phenyl] -9a-methyl-2- (4-pyridyl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8 -Triketone (1 stable delayed isomer = entity B) (MS: 506.2, 508.1 (M + H + )).
實例79Example 79
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-甲氧基乙基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-methoxyethyl) -9a-methyl-4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
在0℃下,向(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(60mg,0.147mmol)含於DMF(2ml)中之溶液添加60%氫化鈉之礦物油懸浮液(12mg,0.3mmol,2eq.)。攪拌該反應10min並添加2-溴-2-甲氧基乙烷(61mg,42μl,0.44mmol,3eq.)。在0℃下攪拌該溶液2h,然後升溫至室溫並攪拌1h。用水淬滅該反應混合物。用乙酸乙酯/水之標準處理後,使有機層經MgSO4乾燥並在真空中濃縮。藉由急驟層析(SiO2(20g)),使用20%至100%乙酸乙酯/庚烷梯度來純化粗物質。獲得呈白色固體之標題化合物(18mg,26%產率),MS:m/e=468.2(M+H+)。 To (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl at 0 ° C ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione (60 mg, 0.147 mmol) in DMF (2 ml) was added with 60% hydrogenation Suspension of sodium in mineral oil (12 mg, 0.3 mmol, 2 eq.). The reaction was stirred for 10 min and 2-bromo-2-methoxyethane (61 mg, 42 μl, 0.44 mmol, 3 eq.) Was added. The solution was stirred at 0 ° C for 2h, then warmed to room temperature and stirred for 1h. The reaction mixture was quenched with water. With ethyl acetate / water treatment standards, the organic layer was dried over MgSO 4 and concentrated in vacuo. By flash chromatography (SiO 2 (20g)), the crude material was purified using 20-100% ethyl acetate / heptane gradient. The title compound was obtained as a white solid (18 mg, 26% yield), MS: m / e = 468.2 (M + H + ).
實例80Example 80
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(3-甲氧基丙基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (3-methoxypropyl) -9a-methyl-4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例79中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及1-溴-3-甲氧基丙烷獲得呈白色結晶固體之標題化合物,MS:m/e=482.2(M+H+)。 Using a chemical action similar to that described in Example 79, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 4, step 2) and 1-bromo-3-methoxypropane to give the title as a white crystalline solid Compound, MS: m / e = 482.2 (M + H + ).
實例81Example 81
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2,2,2-三氟乙基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2,2,2-trifluoroethyl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
在室溫下,向(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(60mg,0.147mmol)及三氟甲磺酸2,2,2-三氟乙酯(61mg,38μl,0.26mmol,1.8eq.)含於DMF(2ml)中之溶液添加K2CO3(61mg,0.44mmol,3eq.)。攪拌該反應10min並添加2-溴-2-甲氧基乙烷(61mg,42μl,0.44mmol,3eq.)。在室溫下攪拌該溶液1h,然後升溫至65℃並攪拌6h。然後添加三氟甲磺酸2,2,2-三氟乙酯(20μl)並在65℃下攪拌該反應16h。添加另一份20μl三氟甲磺酸2,2,2-三氟乙酯,並在65℃下攪拌該混合物1h。用水淬滅反應混合物。在用乙酸乙酯/水標準處理之後,經MgSO4乾燥有機層,並在真空中濃縮。藉由急驟層析(SiO2(20g)),使用10%至100%乙酸乙酯/庚烷梯度,來純化並自未反應之起始物質分離粗物質。獲得呈白色結晶固體之標題化合物,MS:m/e=492.2(M+H+)。 To (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione (60 mg, 0.147 mmol) and triflate 2,2,2-tris A solution of fluoroethyl ester (61 mg, 38 μl, 0.26 mmol, 1.8 eq.) In DMF (2 ml) was added with K 2 CO 3 (61 mg, 0.44 mmol, 3 eq.). The reaction was stirred for 10 min and 2-bromo-2-methoxyethane (61 mg, 42 μl, 0.44 mmol, 3 eq.) Was added. The solution was stirred at room temperature for 1 h, then warmed to 65 ° C and stirred for 6 h. Then 2,2,2-trifluoroethyl triflate (20 μl) was added and the reaction was stirred at 65 ° C. for 16 h. Another 20 μl portion of 2,2,2-trifluoroethyl triflate was added, and the mixture was stirred at 65 ° C. for 1 h. The reaction mixture was quenched with water. After the treatment with ethyl acetate / water standard, the organic layer was dried over MgSO 4, and concentrated in vacuo. By flash chromatography (SiO 2 (20g)), using 10-100% ethyl acetate / heptane gradient, and purified from the unreacted starting material was separated and the crude material. The title compound was obtained as a white crystalline solid, MS: m / e = 492.2 (M + H + ).
實例82Example 82
4-[(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-基]丁酸乙酯4-[(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-1,6,8-trisoxy-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidin-2-yl] butyric acid ethyl ester
在室溫下,向(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步 驟2)(55mg,0.134mmol)及4-溴丁酸乙酯(52mg,39μl,0.27mmol,2.0eq.)含於DMF(1.5ml)中之溶液添加Cs2CO3(88mg,0.27mmol,2.0eq.)。在70℃下攪拌該反應16h。用水淬滅反應混合物。在用乙酸乙酯/水標準處理之後,經MgSO4乾燥有機層並在真空中濃縮。藉由急驟層析(SiO2(20g)),使用10%至100%乙酸乙酯/庚烷梯度,來純化並自未反應之起始物質分離粗物質。獲得呈淺黃色蠟質固體之標題化合物,MS:m/e=524.3(M+H+)。 To (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl ) -4,9-dihydro -3H- pyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4 step 2) (55mg, 0.134mmol) and 4-bromo-butoxy Cs 2 CO 3 (88 mg, 0.27 mmol, 2.0 eq.) Was added to a solution of ethyl acetate (52 mg, 39 μl, 0.27 mmol, 2.0 eq.) In DMF (1.5 ml). The reaction was stirred at 70 ° C for 16h. The reaction mixture was quenched with water. After the treatment with ethyl acetate / water standards, and the organic layer was dried and concentrated in vacuo MgSO 4. By flash chromatography (SiO 2 (20g)), using 10-100% ethyl acetate / heptane gradient, and purified from the unreacted starting material was separated and the crude material. The title compound was obtained as a pale yellow waxy solid, MS: m / e = 524.3 (M + H + ).
實例83Example 83
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(間-甲苯基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (m-tolylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
在室溫下,向(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1H-吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)(50mg,0.122mmol)及1-(溴甲基)-3-甲基苯(27mg,20μl,0.147mmol,1.2eq.)含於DMF(1.8ml)中之溶液添加Cs2CO3(80mg,0.24mmol,2.0eq.)。在室溫下攪拌該反應24h。用水淬滅反應混合物。在用乙酸乙酯/水標準處理之後,經MgSO4乾燥有機層並在真空中濃縮。藉由急驟層析(SiO2(20g)),使用10%至80%乙酸乙酯/庚烷梯度,來純化並自未反應之起始物質分離粗物質。獲得呈白色固體之標題化合物(59mg,94%),MS:m/e=514.3(M+H+)。 To (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1H-pyrazol-4-yl ) -4,9-dihydro -3H- pyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 1) (50mg, 0.122mmol) and 1- (bromomethyl A solution of methyl) -3-methylbenzene (27 mg, 20 µl, 0.147 mmol, 1.2 eq.) In DMF (1.8 ml) was added with Cs 2 CO 3 (80 mg, 0.24 mmol, 2.0 eq.). The reaction was stirred at room temperature for 24 h. The reaction mixture was quenched with water. After the treatment with ethyl acetate / water standards, and the organic layer was dried and concentrated in vacuo MgSO 4. By flash chromatography (SiO 2 (20g)), using 10-80% ethyl acetate / heptane gradient, and purified from the unreacted starting material was separated and the crude material. The title compound was obtained as a white solid (59 mg, 94%), MS: m / e = 514.3 (M + H + ).
實例84Example 84
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(對-甲苯基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (p-tolylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及1-(溴甲基)-4-甲基苯獲得呈白色結晶固體之標題化合物,MS:m/e=514.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 1) and 1- (bromomethyl) -4-methylbenzene obtained as a white The title compound as a crystalline solid, MS: m / e = 514.3 (M + H + ).
實例85Example 85
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(鄰-甲苯基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (o-tolylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及1-(溴甲基)-2-甲基苯獲得呈白色結晶固體之標題化合物,MS:m/e=514.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 1 ) and 1- (bromomethyl) -2-methylbenzene were obtained as white crystals The title compound as a solid, MS: m / e = 514.3 (M + H + ).
實例86Example 86
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(2,6-二甲基苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-[(2,6-dimethylphenyl) methyl] -9a-methyl -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-(溴甲基)-1,3-二甲基苯獲得呈白色固體之標題化合物,MS:m/e=528.4(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, Obtained from 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 1 ) and 2- (bromomethyl) -1,3-dimethylbenzene The title compound as a white solid, MS: m / e = 528.4 (M + H + ).
實例87Example 87
(9aRS)-2-[(2-氯苯基)甲基]-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -2-[(2-chlorophenyl) methyl] -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及1-(溴甲基)-2-氯苯獲得呈白色固體之標題化合物,MS:m/e=534.3,536.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 1) and 1- (bromomethyl) -2-chlorobenzene was obtained as a white solid Title compound, MS: m / e = 534.3, 536.3 (M + H + ).
實例88Example 88
(9aRS)-2-[(3-氯苯基)甲基]-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -2-[(3-chlorophenyl) methyl] -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及1-(溴甲基)-3-氯苯獲得呈白色固體之標題化合物,MS:m/e=534.3,536.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 1 ) and 1- (bromomethyl) -3-chlorobenzene were obtained as a white solid Title compound, MS: m / e = 534.3, 536.3 (M + H + ).
實例89Example 89
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(2-氟苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-[(2-fluorophenyl) methyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及1-(溴甲基)-2-氟苯獲得呈白色結晶固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 2 ) and 1- (bromomethyl) -2-fluorobenzene to give a white crystalline solid Title compound, MS: m / e = 518.3 (M + H + ).
實例90Example 90
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(3-氟苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-[(3-fluorophenyl) methyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及1-(溴甲基)-3-氟苯獲得呈白色固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 2) and 1- (bromomethyl) -3-fluorophenyl obtained as a white solid Title compound, MS: m / e = 518.3 (M + H + ).
實例91Example 91
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-[(4-氟苯基)甲基]-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2-[(4-fluorophenyl) methyl] -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及1-(溴甲基)-3-氟苯獲得呈白色固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 2) and 1- (bromomethyl) -3-fluorophenyl obtained as a white solid Title compound, MS: m / e = 518.3 (M + H + ).
實例92Example 92
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(2-吡啶基(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (2-pyridyl 甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(Methyl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及2-(溴甲基)吡啶氫溴酸鹽獲得呈淺黃色結晶固體之標題化合物,MS:m/e=501.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 1) and 2- (bromomethyl) pyridine hydrobromide obtained as a pale yellow The title compound as a crystalline solid, MS: m / e = 501.3 (M + H + ).
實例93Example 93
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及3-(溴甲基)吡啶氫溴酸鹽獲得呈白色固體之標題化合物,MS:m/e=501.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 1 ) and 3- (bromomethyl) pyridine hydrobromide were obtained as a white solid Title compound, MS: m / e = 501.3 (M + H + ).
實例94Example 94
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(4-吡啶基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (4-pyridylmethyl) -4,9-dihydro -3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-(溴甲基)吡啶氫溴酸鹽獲得呈淺黃色固體之標題化合物,MS:m/e=501.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 1) and 4- (bromomethyl) pyridine hydrobromide obtained as a pale yellow The title compound as a solid, MS: m / e = 501.3 (M + H + ).
實例95Example 95
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(嘧啶-4-基甲基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (pyrimidin-4-ylmethyl) -4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例83中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-(溴甲基)嘧啶氫溴酸鹽獲得呈淺黃色固體之標題化合物,MS:m/e=502.3(M+H+)。 Using a chemical action similar to that described in Example 83, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 1) and 4- (bromomethyl) pyrimidine hydrobromide obtained as a pale yellow The title compound as a solid, MS: m / e = 502.3 (M + H + ).
實例96Example 96
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[(1-甲基吡唑-4-基)甲基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-[(1-methylpyrazol-4-yl) methyl ] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例79中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟1)及4-(溴甲基)-1-甲基-1H-吡唑氫溴酸鹽獲得呈淺棕色固體之標題化合物,MS:m/e=504.3(M+H+)。 Using a chemical action similar to that described in Example 79, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 1 ) and 4- (bromomethyl) -1-methyl-1H-pyrazole Hydrobromide gave the title compound as a light brown solid, MS: m / e = 504.3 (M + H + ).
實例97Example 97
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[(2-甲基吡唑-3-基)甲基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2-[(2-methylpyrazol-3-yl) methyl ] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例79中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮 (實例4步驟2)及5-(溴甲基)-1-甲基-1H-吡唑獲得呈淺黃色固體之標題化合物,MS:m/e=504.3(M+H+)。 Using a chemical action similar to that described in Example 79, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4, step 2 ) and 5- (bromomethyl) -1-methyl-1H-pyrazole The title compound was obtained as a pale yellow solid, MS: m / e = 504.3 (M + H + ).
實例98Example 98
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-2-(2-咪唑-1-基乙基)-9a-甲基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -2- (2-imidazol-1-ylethyl) -9a-methyl-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例79中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-(溴甲基)-1-甲基-1H-吡唑獲得呈白色固體之標題化合物,MS:m/e=504.2(M+H+)。 Using a chemical action similar to that described in Example 79, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 2) and 5- (bromomethyl) -1-methyl -1H- pyrazol The azole gave the title compound as a white solid, MS: m / e = 504.2 (M + H + ).
實例99Example 99
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-(2-甲基咪唑-1-基)乙基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2- (2-methylimidazol-1-yl) ethyl Yl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例79中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及1-(2-溴乙基)-2-甲基-1H-咪唑氫溴酸鹽獲得呈白色固體之標題化合物,MS:m/e=518.2(M+H+)。 Using a chemical action similar to that described in Example 79, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 4, step 2) and 1- (2-bromoethyl) -2-methyl -1H -Imidazole hydrobromide afforded the title compound as a white solid, MS: m / e = 518.2 (M + H + ).
實例100Example 100
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-(2-甲基吡唑-3-基)乙基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2- (2-methylpyrazol-3-yl) Ethyl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例79中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及5-(2-溴乙基)-1-甲基-1H-吡唑獲得呈淺黃色固體之標題化合物,MS:m/e=518.3(M+H+)。 Using a chemical action similar to that described in Example 79, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 4 step 2) and 5- (2-bromoethyl) -1-methyl-1H- Pyrazole gave the title compound as a pale yellow solid, MS: m / e = 518.3 (M + H + ).
實例101Example 101
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-[2-(1-甲基吡唑-4-基)乙基]-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- [2- (1-methylpyrazol-4-yl) Ethyl] -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例79中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例4步驟2)及4-(2-溴乙基)-1-甲基-1H-吡唑獲得呈白色固體之標題化合物,MS:m/e=518.2(M+H+)。 Using a chemical action similar to that described in Example 79, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (example 4 step 2) and 4- (2-bromoethyl) -1-methyl-1H- Pyrazole gave the title compound as a white solid, MS: m / e = 518.2 (M + H + ).
實例102Example 102
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:1-[(E)-肉桂基]氧基-3-甲氧基-丙-2-醇:Step 1: 1-[(E) -Cinnamyl] oxy-3-methoxy-propan-2-ol:
在0℃下,將NaH(60%含於油中)(5.44g,136.2mmol)添加至反式-肉桂醇(18.27g,136.2mmol)含於THF(150ml)中之經攪拌溶液並在25℃下攪拌該反應混合物30min。然後將縮水甘油基甲基醚(10g,113.5mmol)添加至該反應混合物並在70℃下攪拌該反應混合物16h。用水淬滅該反應混合物,並用乙酸乙酯(2 x 250ml)萃取。用鹽水清洗 合併的有機層,經Na2SO4乾燥,並濃縮。藉由在矽膠上之管柱層析(10至12% EtOAc/己烷),純化所得粗物質。獲得呈黃色液體之標題化合物(8.4g,25%)。 NaH (60% in oil) (5.44 g, 136.2 mmol) was added to the stirred solution of trans-cinnamyl alcohol (18.27 g, 136.2 mmol) in THF (150 ml) at 0 ° C and the temperature was 25 ° C. The reaction mixture was stirred at 30 ° C for 30 min. Glycidyl methyl ether (10 g, 113.5 mmol) was then added to the reaction mixture and the reaction mixture was stirred at 70 ° C. for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x 250 ml). The combined organic layers were washed with brine, dried over Na 2 SO 4, and concentrated. The resulting crude material was purified by column chromatography on silica gel (10 to 12% EtOAc / hexane). The title compound was obtained as a yellow liquid (8.4 g, 25%).
步驟2:1-[(E)-肉桂基]氧基-3-甲氧基-丙-2-酮:Step 2: 1-[(E) -Cinnamyl] oxy-3-methoxy-propan-2-one:
在25℃下,將戴斯-馬丁高碘烷(6.93g,16.4mmol)添加至1-[(E)-肉桂基]氧基-3-甲氧基-丙-2-醇(實例102步驟1)(2.42g,10.9mmol)含於二氯甲烷(60ml)中之經攪拌溶液,並在25℃下攪拌該反應混合物3h,用水淬滅並用二氯甲烷(2 x 60ml)萃取。用飽和NaHCO3水溶液及鹽水清洗合併的有機層,經Na2SO4乾燥,並濃縮。藉由在矽膠上之管柱層析(15% EtOAc/己烷)純化所得粗物質。獲得呈黃色油之標題化合物(2.00g,83%)。 At 25 ℃, Dess - Martin periodinane (6.93g, 16.4mmol) was added to 1 - [(E) - cinnamyl]-3-methoxy - propan-2-ol (Examples 102 Step 1 ) (2.42 g, 10.9 mmol) of a stirred solution in dichloromethane (60 ml), and the reaction mixture was stirred at 25 ° C for 3 h, quenched with water and extracted with dichloromethane (2 x 60 ml). The combined organic layers were washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO 4, and concentrated. The resulting crude material was purified by column chromatography on silica (15% EtOAc / hexane). The title compound was obtained as a yellow oil (2.00 g, 83%).
步驟3:(Z)-3-[[(E)-肉桂基]氧基甲基]-4-甲氧基-丁-2-烯酸乙酯:Step 3: (Z) -3-[[(E) -Cinnamyl] oxymethyl] -4-methoxy-but-2-enoic acid ethyl ester:
向1-[(E)-肉桂基]氧基-3-甲氧基-丙-2-酮(實例102步驟2)(3.00g,13.6mmol)含於二氯甲烷(150ml)中之溶液添加(乙酯基亞甲基)三苯基-磷烷(9.50g,27.3mmol)並在25℃下攪拌該反應混合物24h。蒸發溶劑,並藉由管柱層析(10至15% EtOAc/己烷)純化所得粗物質。獲得呈淺黃色油之標題化合物(3.26g,82%),MS:m/e=291.3(M+H+)。 The 1 - [(E) - cinnamyl]-3-methoxy - propan-2-one (Step 102 Examples 2) (3.00g, 13.6mmol) in methylene chloride containing solution (150ml) of the (Ethylmethylene) triphenyl-phosphane (9.50 g, 27.3 mmol) was added and the reaction mixture was stirred at 25 ° C for 24 h. The solvent was evaporated and the resulting crude material was purified by column chromatography (10 to 15% EtOAc / hexane). The title compound was obtained as a pale yellow oil (3.26 g, 82%), MS: m / e = 291.3 (M + H + ).
步驟4:(3RS)-3-胺基-3-[[(E)-肉桂基]氧基甲基]-4-甲氧基-丁酸乙酯:Step 4: (3RS) -3-Amino-3-[[(E) -cinnamyl] oxymethyl] -4-methoxy-butyric acid ethyl ester:
在密封管中,將(Z)-3-[[(E)-肉桂基]氧基甲基]-4-甲氧基-丁-2-烯 酸乙酯(實例102步驟3)(3.62g,12.5mmol)溶解於NH3含於乙醇(4ml)中之飽和溶液中,在90℃下加熱其持續24h。蒸發溶劑,並藉由管柱層析(EtOAc)純化所得粗物質。獲得呈黃色油之標題化合物(1.9g,85%,基於回收的起始物質計),MS:m/e=307.9(M+H+)。 In a sealed tube, the (Z) -3 - [[( E) - cinnamyl] oxymethyl] -4-methoxy - (Examples 102 Step 3) but-2-enoate (3.62 g, 12.5 mmol) was dissolved in a saturated solution of NH 3 in ethanol (4 ml), and it was heated at 90 ° C. for 24 h. The solvent was evaporated and the resulting crude material was purified by column chromatography (EtOAc). The title compound was obtained as a yellow oil (1.9 g, 85%, based on the recovered starting material), MS: m / e = 307.9 (M + H + ).
步驟5:(3RS)-3-[[(E)-肉桂基]氧基甲基]-3-[[2,6-二氟-4-(2-苯基乙炔基)苯基]-胺甲醯基胺基]-4-甲氧基-丁酸乙酯:Step 5: (3RS) -3-[[(E) -cinnamyl] oxymethyl] -3-[[2,6-difluoro-4- (2-phenylethynyl) phenyl] -amine Formamylamino] -4-methoxy-butyric acid ethyl ester:
在25℃下,將三光氣(1.29g,4.37mmol)添加至2,6-二氟-4-苯基乙炔基-苯基胺(實例1步驟1)(1.00g,4.37mmol)含於甲苯(100ml)中之經攪拌溶液並在90℃下攪拌該反應混合物4h。蒸發溶劑,並用二氯甲烷(50ml)稀釋所得異氰酸酯,並在0℃下,添加至(3RS)-3-胺基-3-[[(E)-肉桂基]氧基甲基]-4-甲氧基-丁酸乙酯(實例102步驟4)(1.34g,4.37mmol)及Et3N(1.82ml,13.1mmol)含於二氯甲烷(30ml)中之經攪拌溶液。然後,在室溫下攪拌該反應混合物16h。用二氯甲烷稀釋該反應混合物並用水清洗。有機層經Na2SO4乾燥並濃縮。藉由在矽膠上之管柱層析(30至40% EtOAc/己烷),純化所得粗物質,產生呈灰白色固體之標題化合物(1.38g,56%),MS:m/e=563.2(M+H+)。 Add triphosgene (1.29 g, 4.37 mmol) to 2,6-difluoro-4-phenylethynyl-phenylamine ( Example 1 step 1 ) (1.00 g, 4.37 mmol) in toluene at 25 ° C. (100 ml) of the stirred solution and the reaction mixture was stirred at 90 ° C for 4 h. The solvent was evaporated, and the obtained isocyanate was diluted with dichloromethane (50 ml) and added to (3RS) -3-amino-3-[[(E) -cinnamyl] oxymethyl] -4- at 0 ° C. methoxy - butyric acid ethyl ester (Examples 102 step 4) (1.34g, 4.37mmol) and Et 3 N (1.82ml, 13.1mmol) in dichloromethane containing the (30ml) was stirred. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with water. 2 SO 4 dried and concentrated the organic layer was Na. The obtained crude material was purified by column chromatography on silica gel (30 to 40% EtOAc / hexane) to give the title compound (1.38 g, 56%) as an off-white solid, MS: m / e = 563.2 (M + H + ).
步驟6:(6RS)-6-[[(E)-肉桂基]氧基甲基]-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-(甲氧基甲基)六氫嘧啶-2,4-二酮:Step 6: (6RS) -6-[[((E) -cinnamyl] oxymethyl] -3- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -6- (Methoxymethyl) hexahydropyrimidine-2,4-dione:
在0℃下,將(3RS)-3-[[(E)-肉桂基]氧基甲基]-3-[[2,6-二氟-4-(2-苯基乙炔基)-苯基]-胺甲醯基胺基]-4-甲氧基-丁酸乙酯(實例102步驟5)(3.00g,5.34mmol)含於THF(30ml)中之溶液添加至經充分攪拌之 NaH(60%含於油中)(320mg,8.01mmol)含於THF(40ml)中之溶液,並在25℃下攪拌該反應混合物2h。用水淬滅反應混合物,並用EtOAc(2 x 120ml)萃取。合併的有機層經Na2SO4乾燥並蒸發。藉由在矽膠上之管柱層析(20至30% EA/己烷),純化所得粗物質,獲得呈灰白色固體之標題化合物(2.50g,91%),MS:m/e=517.0(M+H+)。 At 0 ° C, (3RS) -3-[[(E) -cinnamyl] oxymethyl] -3-[[2,6-difluoro-4- (2-phenylethynyl) -benzene yl] - amino acyl carbamoyl] -4-methoxy - butyric acid ethyl ester (Examples 102 step 5) (3.00g, 5.34mmol) contained in the THF (30ml) was added to the stirred sufficiently A solution of NaH (60% in oil) (320 mg, 8.01 mmol) in THF (40 ml), and the reaction mixture was stirred at 25 ° C for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2 x 120 ml). 2 SO 4 and evaporated and dried the combined organic layers were dried over Na. The obtained crude material was purified by column chromatography on silica gel (20 to 30% EA / hexane) to obtain the title compound (2.50 g, 91%) as an off-white solid, MS: m / e = 517.0 (M + H + ).
步驟7:N-[2-[(6RS)-6-[[(E)-肉桂基]氧基甲基]-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-(甲氧基甲基)-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯:Step 7: N- [2-[(6RS) -6-[[(E) -cinnamyl] oxymethyl] -3- [2,6-difluoro-4- (2-phenylethynyl) Phenyl] -6- (methoxymethyl) -2,4-dioxo-hexahydropyrimidin-1-yl] ethyl] aminocarboxylic acid third butyl ester:
向(6RS)-6-[[(E)-肉桂基]氧基甲基]-3-[2,6-二氟-4-(2-苯基乙炔基)-苯基]-6-(甲氧基甲基)六氫嘧啶-2,4-二酮(實例102步驟6)(1.00g,1.94mmol)含於DMF(6.7ml)中之溶液添加(2-溴乙基)胺基甲酸第三丁酯(0.868g,3.87mmol)及碳酸銫(1.39g,4.26mmol)。在55℃下攪拌該反應混合物16h。在真空中蒸發溶劑,並將殘餘物溶於60ml EtOAc/庚烷3:1中。過濾除去不可溶物質,並用水、鹽水清洗濾液,經Na2SO4乾燥,並濃縮。藉由在矽膠上之急驟層析,使用0至40% EtOAc/己烷梯度,純化所得粗物質,獲得呈白色發泡體之標題化合物(1.18g,92%),MS:m/e=560.2((M-Boc)+H+)。 (6RS) -6-[[(E) -cinnamyl] oxymethyl] -3- [2,6-difluoro-4- (2-phenylethynyl) -phenyl] -6- ( methoxymethyl) hexahydro-2,4-dione (step 102 Examples 6) (1.00g, 1.94mmol) contained in DMF (6.7ml) was added a solution of (2-bromoethyl) amine Third butyl formate (0.868 g, 3.87 mmol) and cesium carbonate (1.39 g, 4.26 mmol). The reaction mixture was stirred at 55 ° C for 16 h. The solvent was evaporated in vacuo and the residue was dissolved in 60 ml of EtOAc / heptane 3: 1. The insoluble material was removed by filtration, and the filtrate was washed with water and brine, dried over Na 2 SO 4 , and concentrated. The obtained crude material was purified by flash chromatography on silica gel using a gradient of 0 to 40% EtOAc / hexanes to obtain the title compound (1.18 g, 92%) as a white foam, MS: m / e = 560.2 ((M-Boc) + H +).
步驟8:N-[2-[(6RS)-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-(羥基甲基)-6-(甲氧基甲基)-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯:Step 8: N- [2-[(6RS) -3- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -6- (hydroxymethyl) -6- (methoxy Methyl) -2,4-dioxo-hexahydropyrimidin-1-yl] ethyl] amino butyl terephthalate:
向N-[2-[(6RS)-6-[[(E)-肉桂基]氧基甲基]-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-(甲氧基甲基)-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯(實例102步驟7)(1.150g,1.74mmol)含於硝基甲烷(30ml)中之溶液添加氯化鈰(III)七水合物(0.714g,1.92mmol)、碘化鈉(0.287g,1.92mmol)及1,3-丙二醇(0.208g,194ul,1.92mmol)。在100℃下攪拌該混合物32h。在真空中濃縮該反應混合物,並溶於60ml二氯甲烷/MeOH 93:7中。過濾除去固體,並用水清洗濾液。濃縮有機相,並藉由在Silica-Aminophase管柱上之急驟層析,使用1:1 EtOAc/庚烷,然後用EtOAc及最後用EtOAc/MeOH 95:5作為洗脫劑,純化殘餘物,產生490mg含有去第三丁氧基羰基化物質且難以分離雜質之淺黃色固體。將此物質溶於THF(22ml)、三乙胺(0.168g,231ul,1.66mmol)中並添加二碳酸二-第三丁酯(0.289g,1.33mmol),並在25℃下攪拌該混合物2h。濃縮該混合物,並藉由在矽膠上之急驟層析,使用0至100% EtOAc/庚烷梯度純化殘餘物,產生呈白色固體之標題化合物(0.362g,38%),MS:m/e=444.2((M-Boc)+H+)。 N- [2-[(6RS) -6-[[(E) -cinnamyl] oxymethyl] -3- [2,6-difluoro-4- (2-phenylethynyl) phenyl ] -6- (methoxymethyl) -2,4-dioxo-hexahydropyrimidin-1-yl] ethyl] aminobutyl third butyl ester ( Example 102, step 7 ) (1.150 g, 1.74 mmol) in nitromethane (30 ml) was added cerium (III) chloride heptahydrate (0.714 g, 1.92 mmol), sodium iodide (0.287 g, 1.92 mmol) and 1,3-propanediol (0.208 g). , 194ul, 1.92mmol). The mixture was stirred at 100 ° C for 32 h. The reaction mixture was concentrated in vacuo and dissolved in 60 ml of dichloromethane / MeOH 93: 7. The solid was removed by filtration, and the filtrate was washed with water. The organic phase was concentrated and the residue was purified by flash chromatography on a Silica-Aminophase column using 1: 1 EtOAc / heptane, then with EtOAc and finally with EtOAc / MeOH 95: 5 as the eluent, yielding 490 mg of a pale yellow solid containing a third tert-butoxycarbonylated substance and difficult to separate impurities. This material was dissolved in THF (22 ml), triethylamine (0.168 g, 231 ul, 1.66 mmol) and di-tertiary butyl dicarbonate (0.289 g, 1.33 mmol) was added, and the mixture was stirred at 25 ° C for 2 h . The mixture was concentrated and the residue was purified by flash chromatography on silica using a gradient from 0 to 100% EtOAc / heptane to give the title compound as a white solid (0.362 g, 38%), MS: m / e = 444.2 ((M-Boc) + H +).
步驟9:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-甲酸第三丁酯:Step 9: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -1,6,8-trilateral oxygen -Butyl-4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-2-carboxylic acid tert-butyl ester:
向N-[2-[(6RS)-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-(羥基甲基)-6-(甲氧基甲基)-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯(實例102步驟8)(0.260g,0.478mmol)含於二氯甲烷(11ml)及DMF (1.6ml)中之溶液添加0.900g粉狀活性4A分子篩、重鉻酸吡錠(0.675g,1.79mmol,3.75eq.)及乙酸(0.124g,118ul,2.06mmol)。在室溫下攪拌該混合物16h。用50ml EtOAc稀釋該反應,然後添加Speedex(約5g),並攪拌該懸浮液5min。過濾除去固體,並用50ml EtOAc清洗。濾液經Na2SO4乾燥,並蒸發。藉由在矽膠上之管柱層析,使用0至80% EtOAc/庚烷梯度,純化所得粗物質,獲得呈白色固體之標題化合物(0.114g,54%),MS:m/e=440.2((M-Boc)+H+)。 N- [2-[(6RS) -3- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -6- (hydroxymethyl) -6- (methoxymethyl yl) -2,4-oxo - hexahydro-1-yl] ethyl] carbamic acid tert-butyl ester (Example 102 step solid 8) (0.260g, 0.478mmol) in dichloromethane containing ( 11ml) and DMF (1.6ml) were added with 0.900g of powdered active 4A molecular sieve, pyridinium dichromate (0.675g, 1.79mmol, 3.75eq.) And acetic acid (0.124g, 118ul, 2.06mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with 50 ml of EtOAc, then Speedex (about 5 g) was added and the suspension was stirred for 5 min. The solids were removed by filtration and washed with 50 ml of EtOAc. The filtrate was dried over Na 2 SO 4, and evaporated. The obtained crude material was purified by column chromatography on silica gel using a gradient of 0 to 80% EtOAc / heptane to obtain the title compound (0.114 g, 54%) as a white solid, MS: m / e = 440.2 ( (M-Boc) + H +).
步驟10:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 10: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2,3,4,9-tetra Hydropyrazino [1,2-c] pyrimidine-1,6,8-trione:
將(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-甲酸第三丁酯(實例102步驟9)(0.140g,0.259mmol)含於7ml二氯甲烷中之溶液冷卻至0至2℃。然後添加4N HCl/二噁烷溶液(0.519ml,2.08mmol,8eq.)。在室溫下攪拌2h之後,用20ml二氯甲烷稀釋該溶液,藉由添加5ml 5% NaHCO3溶液淬滅,接著用二氯甲烷萃取。用鹽水清洗有機層,經Na2SO4乾燥並濃縮,產生呈結晶白色固體之標題化合物(0.109g,96%),MS:m/e=440.2(M+H+)。 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -1,6,8-trisoxy- A solution of 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-2-carboxylic acid third butyl ester ( Example 102, step 9 ) (0.140 g, 0.259 mmol) in 7 ml of dichloromethane Cool to 0 to 2 ° C. Then a 4N HCl / dioxane solution (0.519 ml, 2.08 mmol, 8 eq.) Was added. After stirring for 2h at room temperature, the solution was diluted with 20ml of dichloromethane, by adding 5ml 5% NaHCO 3 solution was quenched and then extracted with dichloromethane. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to give the title compound (0.109g, 96%) of a crystalline white solid, MS: m / e = 440.2 (M + H +).
步驟11:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 11: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (3-pyridyl)- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例102步驟10)及3-碘吡啶獲得呈白色固體之標題化合物,MS:m/e=517.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 102, step 10) and 3-iodopyridine to give the title compound as a white solid, MS: m / e = 517.2 (M + H + ).
實例103Example 103
(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
藉由對掌性HPLC,在Reprosil Chiral-NR管柱上,使用(己烷/EtOH/NH4OAc-70/30/0.1%)作為洗脫劑,實現實例102之外消旋物之對掌性分離,其產生呈白色固體之(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:517.3(M+H+));及呈白色固體之(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:517.3(M+H+))。 Using palm HPLC on a Reprosil Chiral-NR column using (hexane / EtOH / NH 4 OAc-70 / 30 / 0.1%) as the eluent, the alignment of the racemate of Example 102 was achieved. Isolated, which gave (9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- ( 3-pyridyl) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidin-1,6,8-trione (MS: 517.3 (M + H + )); and white (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (3-pyridyl) -4 as a solid , 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione (MS: 517.3 (M + H + )).
實例104Example 104
(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (1-methylpyrazole-4- ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例102步驟10)及4-碘-1-甲基-1H-吡唑獲得呈白色固體之標題化合物,MS:m/e=520.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 102, step 10) and 4-iodo-1-methyl-1H-pyridine The azole gave the title compound as a white solid, MS: m / e = 520.2 (M + H + ).
實例105Example 105
(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (1-methylpyrazole-4- ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
藉由在Chiralpak AD管柱上,使用(庚烷/EtOH/NH4OAc-60/40/0.1%)作為洗脫劑,對掌性HPLC分離外消旋(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-(甲氧基甲基)-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例104),獲得呈灰白色固體之標題化合物,MS:m/e=520.2(M+H+)。 Separation of racemic (9aRS) -7- [2,6 for palm HPLC by using (heptane / EtOH / NH 4 OAc-60 / 40 / 0.1%) as eluent on a Chiralpak AD column. -Difluoro-4- (2-phenylethynyl) phenyl] -9a- (methoxymethyl) -2- (1-methylpyrazol-4-yl) -4,9-dihydro- 3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione ( Example 104) , the title compound was obtained as an off-white solid, MS: m / e = 520.2 (M + H + ).
實例106Example 106
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:1-烯丙氧基丁-2-醇:Step 1: 1-allyloxybut-2-ol:
在0℃下,將1,2-環氧基丁烷(19.33g,332.82mmol)含於THF(100ml)中之溶液添加至NaH(13.31g,332.82mmol)含於THF(130ml)中之懸浮液並在25℃下攪拌反應混合物30min。然後在25℃下,添加烯丙醇(20.0g,277.35mmol)含於THF(70ml)中之溶液,並使該反應混合物回流16h。用水淬滅及用EtOAc(2 x 500ml)萃取之後,合併的有機層經Na2SO4乾燥,並濃縮。藉由在矽膠上之管柱層析(15至20% EtOAc/己烷)純化所得粗物質。獲得呈黃色液體之標題化合物(13g,36%)。 A solution of 1,2-epoxybutane (19.33 g, 332.82 mmol) in THF (100 ml) was added to a suspension of NaH (13.31 g, 332.82 mmol) in THF (130 ml) at 0 ° C. The reaction mixture was stirred at 25 ° C for 30 min. A solution of allyl alcohol (20.0 g, 277.35 mmol) in THF (70 ml) was then added at 25 ° C, and the reaction mixture was refluxed for 16 h. After quenched with water and extracted with EtOAc (2 x 500 ml), the combined organic layers were dried over Na 2 SO 4 and concentrated. The resulting crude material was purified by column chromatography on silica (15 to 20% EtOAc / hexane). The title compound was obtained as a yellow liquid (13 g, 36%).
步驟2:1-烯丙氧基丁-2-酮:Step 2: 1-allyloxybutan-2-one:
在25℃下,向1-烯丙氧基-丁-2-醇(實例106步驟1)(5.0g,38.5 mmol)含於二氯甲烷(100ml)中之溶液添加重鉻酸吡錠(20.72g,96.15mmol)並在25℃下攪拌該反應混合物5h,經由矽藻土過濾並濃縮濾液。獲得呈棕色油之標題化合物(4.3g,87%),其足夠純可直接用於下一步驟中。 At 25 ℃, a solution of 1-allyloxy - ol (Examples 106 Step 1) (5.0g, 38.5 mmol) contained in dichloromethane (100ml) was added a solution of the pyrazol ingot dichromate ( 20.72 g, 96.15 mmol) and stirred the reaction mixture at 25 ° C. for 5 h, filtered through celite and concentrated the filtrate. The title compound was obtained as a brown oil (4.3 g, 87%), which was pure enough to be used directly in the next step.
步驟3:(EZ)-3-(烯丙氧基甲基)戊-2-烯酸乙酯:Step 3: (EZ) -3- (Allyloxymethyl) pent-2-enoate:
在0℃下,向NaH(405mg,10.1mmol)含於THF(20ml)中之懸浮液膦醯基乙酸三乙酯(2.62g,11.7mmol)並在25℃下攪拌該反應混合物30min。然後添加1-烯丙氧基-丁-2-酮(實例106步驟2)(1g,7.80mmol)含於THF(5ml)中之溶液並在25℃下攪拌該反應混合物3h。用飽和NH4Cl水溶液淬滅該反應混合物,並用EtOAc(2 x 40ml)萃取。合併的有機層經Na2SO4乾燥,濃縮,並藉由在矽膠上之管柱層析(10至15% EtOAc/己烷)純化所得粗物質。獲得呈黃色液體之標題化合物(1.0g,65%)。 To a suspension of NaH (405 mg, 10.1 mmol) in THF (20 ml) at 0 ° C, phosphinophosphonium triethyl acetate (2.62 g, 11.7 mmol) was stirred and the reaction mixture was stirred at 25 ° C for 30 min. Then add 1- allyloxy - 2-one (step 106 Examples 2) (1g, 7.80mmol) contained in a solution (5ml) in THF and the reaction mixture was stirred 3h at 25 ℃. The reaction mixture was treated with saturated aqueous NH 4 Cl was quenched and extracted with EtOAc (2 x 40ml). The combined organic layers were dried over Na 2 SO 4, concentrated and by column chromatography (10 to 15% EtOAc / hexanes) on silica gel of the crude material obtained was purified. The title compound was obtained as a yellow liquid (1.0 g, 65%).
步驟4:(3RS)-3-(烯丙氧基甲基)-3-胺基-戊酸乙酯:Step 4: (3RS) -3- (allyloxymethyl) -3-amino-valeric acid ethyl ester:
於密封管中,將(EZ)-3-(烯丙氧基甲基)戊-2-烯酸乙酯(實例102步驟3)(2.8g,14.12mmol)溶解於NH3含於乙醇(5ml)中之飽和溶液,在90℃下加熱16h。蒸發溶劑,並藉由在矽膠上之管柱層析(80至100% EtOAc/己烷)純化所得粗物質。獲得呈淺黃色液體之標題化合物(1.5g,49%基於回收之起始物質(1.0g)計)。 In a sealed tube, (EZ) -3- (allyloxymethyl) pent-2-enoic acid ethyl ester (Examples 102 Step 3) (2.8g, 14.12mmol) was dissolved in NH 3 in ethanol containing ( 5ml) and heated at 90 ° C for 16h. The solvent was evaporated and the resulting crude material was purified by column chromatography on silica (80 to 100% EtOAc / hexane). The title compound was obtained as a pale yellow liquid (1.5 g, 49% based on the recovered starting material (1.0 g)).
步驟5:(3RS)-3-(烯丙氧基甲基)-3-[[2,6-二氟-4-(2-苯基乙炔基)苯基]-胺甲醯基胺基]戊酸乙酯:Step 5: (3RS) -3- (allyloxymethyl) -3-[[2,6-difluoro-4- (2-phenylethynyl) phenyl] -aminomethylamidoamino] Ethyl valerate:
在25℃下,將三光氣(2.76g,9.3mmol)添加至2,6-二氟-4-苯基乙炔基-苯基胺(實例1步驟1)(2.13g,9.3mmol)含於甲苯(100ml)中之經攪拌溶液並在90℃下攪拌該反應混合物4h。蒸發溶劑,並用二氯甲烷(50ml)稀釋所得異氰酸酯,並添加至在0℃之(3RS)-3-(烯丙氧基甲基)-3-胺基-戊酸乙酯(實例106步驟4)(2.0g,9.3mmol)及Et3N(3.91ml,27.9mmol)含於二氯甲烷(50ml)中之經攪拌溶液。然後,在25℃下攪拌該反應混合物16h。用二氯甲烷稀釋該反應混合物,並用水清洗。有機層經Na2SO4乾燥,並濃縮。藉由在矽膠上之管柱層析(15% EtOAc/己烷)純化所得粗物質,產生呈灰白色固體之標題化合物(2.0g,46%),MS:m/e=471.1(M+H+)。 Add triphosgene (2.76 g, 9.3 mmol) to 2,6-difluoro-4-phenylethynyl-phenylamine ( Example 1 step 1 ) (2.13 g, 9.3 mmol) in toluene at 25 ° C. (100 ml) of the stirred solution and the reaction mixture was stirred at 90 ° C for 4 h. The solvent was evaporated, and the (50ml) isocyanate was diluted with dichloromethane and added to a 3- (allyloxymethyl) 0 deg.] C of (3RS) -3- amino - pentanoate (step 106 Examples 4) (2.0g, 9.3mmol) and Et 3 N (3.91ml, 27.9mmol) contained in dichloromethane (50ml) was stirred in the solution. The reaction mixture was then stirred at 25 ° C for 16 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over Na 2 SO 4 and concentrated. The obtained crude material was purified by column chromatography on silica gel (15% EtOAc / hexane) to give the title compound (2.0 g, 46%) as an off-white solid, MS: m / e = 471.1 (M + H + ).
步驟6:(6RS)-6-(烯丙氧基甲基)-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-乙基-六氫嘧啶-2,4-二酮:Step 6: (6RS) -6- (allyloxymethyl) -3- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -6-ethyl-hexahydropyrimidine -2,4-dione:
在0℃下,將(3RS)-3-(烯丙氧基甲基)-3-[[2,6-二氟-4-(2-苯基乙炔基)苯基]-胺甲醯基胺基]戊酸乙酯(實例106步驟5)(3.1g,5.51mmol)含於THF(20ml)中之溶液添加至經充分攪拌之NaH(60%含於油中)(0.220g,5.51mmol)含於THF(20ml)中之懸浮液,並在25℃下攪拌該反應混合物2h。用水淬滅反應混合物,並用EtOAc(2 x 200ml)萃取。合併的有機層經Na2SO4乾燥並蒸發。藉由在矽膠上之管柱層析(20% EtOAc/己烷),純化所得粗物質,獲得呈灰白色固體之標題化合物(2.0g,85%),MS:m/e=425.4(M+H+)。 At 0 ° C, (3RS) -3- (allyloxymethyl) -3-[[2,6-difluoro-4- (2-phenylethynyl) phenyl] -carbamoyl amino] pentanoic acid ethyl ester (Examples 106 step 5) (3.1g, 5.51mmol) contained in THF (20ml) was added in to the stirred sufficiently of NaH (60% in oil-containing) (0.220g, 5.51 mmol) in THF (20 ml), and the reaction mixture was stirred at 25 ° C. for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2 x 200 ml). 2 SO 4 and evaporated and dried the combined organic layers were dried over Na. The obtained crude material was purified by column chromatography on silica gel (20% EtOAc / hexane) to obtain the title compound (2.0 g, 85%) as an off-white solid, MS: m / e = 425.4 (M + H + ).
步驟7:N-[2-[(6RS)-6-(烯丙氧基甲基)-3-[2,6-二氟-4-(2-苯基乙Step 7: N- [2-[(6RS) -6- (allyloxymethyl) -3- [2,6-difluoro-4- (2-phenylethyl 炔基)苯基]-6-乙基-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯:Alkynyl) phenyl] -6-ethyl-2,4-dioxo-hexahydropyrimidin-1-yl] ethyl] aminobutyl third butyl ester:
向(3RS)-3-(烯丙氧基甲基)-3-[[2,6-二氟-4-(2-苯基乙炔基)苯基]-胺甲醯基胺基]戊酸乙酯(實例106步驟6)(1.00g,2.36mmol)含於DMF(8.0ml)中之溶液添加(2-溴乙基)胺基甲酸第三丁酯(1.06g,4.71mmol)及碳酸銫(1.69g,5.18mmol)。在55℃下攪拌該反應混合物16h並在70℃下攪拌6h。在真空中蒸發溶劑,並將殘餘物溶於60ml EtOAc/庚烷3:1中。過濾除去不可溶物質,並用水、鹽水清洗濾液,經Na2SO4乾燥並濃縮。藉由在矽膠上之急驟層析,使用0至40% EtOAc/己烷梯度純化所得粗物質,獲得呈淺黃色發泡體之標題化合物(1.34g,92%),MS:m/e=468.3((M-Boc)+H+)。 (3RS) -3- (allyloxymethyl) -3-[[2,6-difluoro-4- (2-phenylethynyl) phenyl] -aminomethylaminoamino] pentanoic acid A solution of ethyl acetate ( step 6 in Example 106 ) (1.00 g, 2.36 mmol) in DMF (8.0 ml) was added (2-bromoethyl) amino butyl formate (1.06 g, 4.71 mmol) and cesium carbonate (1.69 g, 5.18 mmol). The reaction mixture was stirred at 55 ° C for 16h and at 70 ° C for 6h. The solvent was evaporated in vacuo and the residue was dissolved in 60 ml of EtOAc / heptane 3: 1. The insoluble material was removed by filtration, and the filtrate was washed with water and brine, dried over Na 2 SO 4 and concentrated. The obtained crude material was purified by flash chromatography on silica gel using a gradient of 0 to 40% EtOAc / hexane to obtain the title compound (1.34 g, 92%) as a pale yellow foam, MS: m / e = 468.3 ((M-Boc) + H +).
步驟8:N-[2-[(6RS)-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-乙基-6-(羥基甲基)-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯:Step 8: N- [2-[(6RS) -3- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -6-ethyl-6- (hydroxymethyl)- Tert-butyl 2,4-dioxo-hexahydropyrimidin-1-yl] ethyl] aminoformate:
在25ml玻璃壓力容器中,用氬氣流使N-[2-[(6RS)-6-(烯丙氧基甲基)-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-乙基-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯(實例106步驟7)(0.525g,0.925mmol)及1,3-二甲基巴比妥酸(0.289g,1.85mmol)含於甲醇(10ml)中之溶液脫氣,並添加Pd(TPP)4觸媒(53.4mg,46.2μmol,5mol%)。關閉該容器並在80℃下攪拌該混合物3h,然後在室溫下再攪拌16h。濃 縮該混合物,並藉由在矽膠上之急驟層析,使用0至100% EtOAc/庚烷梯度純化殘餘物,產生呈非晶型無色樹脂之標題化合物(0.34g,70%),MS:m/e=428.3((M-Boc)+H+)。 In a 25 ml glass pressure vessel, N- [2-[(6RS) -6- (allyloxymethyl) -3- [2,6-difluoro-4- (2-phenylacetylene) yl) phenyl] -6-ethyl-2,4-oxo - hexahydro-1-yl] ethyl] carbamic acid tert-butyl ester (Examples 106 step 7) (0.525g, 0.925 mmol) and 1,3-dimethylbarbituric acid (0.289g, 1.85mmol) in methanol (10ml). Degas and add Pd (TPP) 4 catalyst (53.4mg, 46.2μmol, 5mol). %). The container was closed and the mixture was stirred at 80 ° C. for 3 h and then at room temperature for another 16 h. The mixture was concentrated and the residue was purified by flash chromatography on silica using a gradient of 0 to 100% EtOAc / heptane to give the title compound (0.34 g, 70%) as an amorphous colorless resin, MS: m /e=428.3((M-Boc)+H+).
步驟9:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-甲酸第三丁酯:Step 9: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-1,6,8-trisoxy-4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-2-carboxylic acid third butyl ester:
向N-[2-[(6RS)-6-(烯丙氧基甲基)-3-[2,6-二氟-4-(2-苯基乙炔基)苯基]-6-乙基-2,4-二側氧基-六氫嘧啶-1-基]乙基]胺基甲酸第三丁酯(實例106步驟8)(0.620g,1.18mmol)含於二氯甲烷(33ml)及DMF(3.5ml)中之溶液添加1.5g粉狀活性4A分子篩、重鉻酸吡錠(1.55g,4.11mmol)及乙酸(0.282g,269μl,4.7mmol)。在室溫下攪拌該混合物16h。用60ml EtOAc稀釋該反應,然後添加Speedex(約5g),並攪拌該懸浮液5min。過濾除去固體,並用60ml EtOAc清洗。濾液經Na2SO4乾燥並蒸發。藉由在矽膠上之管柱層析,使用0至80% EtOAc/庚烷梯度純化所得粗物質,獲得呈白色固體之標題化合物(0.274g,45%),MS:m/e=424.2((M-Boc)+H+)。 N- [2-[(6RS) -6- (allyloxymethyl) -3- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -6-ethyl -2,4-Dioxo-hexahydropyrimidin-1-yl] ethyl] amino carboxylic acid tert-butyl ester ( Example 106, step 8 ) (0.620 g, 1.18 mmol) in dichloromethane (33 ml) and The solution in DMF (3.5 ml) was added with 1.5 g of powdered active 4A molecular sieve, pyridinium dichromate (1.55 g, 4.11 mmol) and acetic acid (0.282 g, 269 μl, 4.7 mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with 60 ml of EtOAc, then Speedex (about 5 g) was added and the suspension was stirred for 5 min. The solids were removed by filtration and washed with 60 ml of EtOAc. 2 SO 4 dried and evaporated filtrate was Na. The obtained crude material was purified by column chromatography on silica gel using a gradient of 0 to 80% EtOAc / heptane to obtain the title compound (0.274 g, 45%) as a white solid, MS: m / e = 424.2 (( M-Boc) + H +).
步驟10:(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 10: (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2,3,4,9-tetrahydropyrazino [ 1,2-c] pyrimidine-1,6,8-trione:
將(9aRS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-1,6,8-三側氧基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-2-甲酸第三丁酯(實例106步驟9)(0.280g,0.535mmol)含於12ml二氯甲烷中之溶液冷卻至0至2℃。然後添加4N HCl之二噁烷溶液(1.07ml,4.28mmol,8equiv.)。在室溫下攪拌2h之後,用20ml二氯甲烷稀釋該溶液,藉由添加5ml 5% NaHCO3溶液淬滅,接著用二氯甲烷萃取。用鹽水清洗有機層,經Na2SO4乾燥,並濃縮,產生呈結晶白色固體之標題化合物(0.221g,98%),MS:m/e=424.2(M+H+)。 (9aRS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-1,6,8-trisoxy-4,9-di hydrogen -3H- pyrazino [1,2-c] pyrimidine-2-carboxylic acid tert-butyl ester solution was cooled (solid Example 106 step 9) (0.280g, 0.535mmol) in 12ml of dichloromethane containing 0 to of 2 ° C. 4N HCl in dioxane (1.07 ml, 4.28 mmol, 8 equiv.) Was then added. After stirring for 2h at room temperature, the solution was diluted with 20ml of dichloromethane, by adding 5ml 5% NaHCO 3 solution was quenched and then extracted with dichloromethane. The organic layer was washed with brine, dried over Na 2 SO 4, and concentrated to yield a crystalline white solid of the title compound (0.221g, 98%), MS : m / e = 424.2 (M + H +).
步驟11:(9aS)-及(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 11: (9aS)-and (9aR) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2,3,4,9-tetra Hydropyrazino [1,2-c] pyrimidine-1,6,8-trione:
藉由對掌性HPLC,使用Chiralpak IE管柱,使用(己烷/EtOH/DCM/Et2N-70/20/10/0.1%)作為洗脫液實現對映異構體之對掌性分離,得到呈淺黃色固體之(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:424.2(M+H+));及呈淺黃色固體之(9aR)-7-[2,6-二氟-4-(2-苯基乙炔基)-苯基]-9a-乙基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:424.2(M+H+))。 Enantiomeric separation of enantiomers was achieved by chiral HPLC using a Chiralpak IE column using (hexane / EtOH / DCM / Et 2 N-70 / 20/10 / 0.1%) as the eluent. (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2,3,4,9-tetrahydro as a pale yellow solid Pyrazino [1,2-c] pyrimidine-1,6,8-trione (MS: 424.2 (M + H + )); and (9aR) -7- [2,6-di Fluoro-4- (2-phenylethynyl) -phenyl] -9a-ethyl-2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8- Triketone (MS: 424.2 (M + H + )).
步驟12:(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 12: (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2- (3-pyridyl) -4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例106步驟11)及3-碘吡啶獲得呈白色固體之標題化合物,MS:m/e=501.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 106, step 11) and 3-iodopyridine to give the title compound as a white solid, MS: m / e = 501.3 (M + H + ).
實例107Example 107
(9aS)-7-[2,6-二氟-4-(2-苯基乙炔基)苯基]-9a-乙基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2- (1-methylpyrazol-4-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-(2- 苯基乙炔基)苯基]-9a-乙基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例106步驟11)及4-碘-1-甲基-1H-吡唑獲得呈白色固體之標題化合物,MS:m/e=504.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- (2-phenylethynyl) phenyl] -9a-ethyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 106, step 11) and 4-iodo-1-methyl-1H-pyrazole to obtain a white solid Title compound, MS: m / e = 504.3 (M + H + ).
實例108Example 108
(9aRS)-7-[2-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aRS) -7- [2-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H-pyrazine Benzo [1,2-c] pyrimidine-1,6,8-trione
步驟1:2-氟-4-苯基乙炔基-苯基胺Step 1: 2-Fluoro-4-phenylethynyl-phenylamine
使用類似於實例1步驟1中所述之化學作用,自2-氟-4-碘苯胺及苯基乙炔獲得呈棕色固體之標題化合物,MS:m/e=212.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 1, the title compound was obtained as a brown solid from 2-fluoro-4-iodoaniline and phenylacetylene, MS: m / e = 212.2 (M + H + ).
步驟2:(9aRS)-7-[2-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 2: (9aRS) -7- [2-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2 -c] pyrimidine-1,6,8-trione:
使用類似於實例1步驟2中所述之化學作用,自2-氟-4-苯基乙炔基-苯基胺(實例107步驟1)及2-[(2RS)-2-甲基-3-側氧基-哌嗪-2-基]乙酸甲酯獲得呈白色固體之標題化合物,MS:m/e=392.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 2 from 2-fluoro-4-phenylethynyl-phenylamine ( Example 107, Step 1) and 2-[(2RS) -2-methyl-3- Oxy-piperazin-2-yl] methyl acetate gave the title compound as a white solid, MS: m / e = 392.2 (M + H + ).
步驟3:(9aRS)-7-[2-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 3: (9aRS) -7- [2-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (3-pyridyl) -4,9-dihydro-3H -Pyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例5中所述之化學作用,自(9aRS)-7-[2-氟-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例107步驟2)及3-碘吡啶獲得呈白色固體之標題化合物,MS:m/e=469.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aRS) -7- [2-fluoro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9 - tetrahydropyrazino [1,2-c] pyrimidine-trione -1,6,8- (Examples 107 step 2) and 3-iodopyridine was obtained as a white solid of the title compound, MS: m / e = 469.3 (M + H + ).
實例109Example 109
(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2- (3-pyridyl) -4,9 -Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:(9aRS)-7-(2,6-二氟-4-碘-苯基)-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 1: (9aRS) -7- (2,6-difluoro-4-iodo-phenyl) -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c] Pyrimidine-1,6,8-trione:
向2,6-二氟-4-碘-苯基胺(3.00g,11.8mmol)含於甲苯(80ml)中之溶液添加CDI(5.72g,35.3mmol)並在110℃下攪拌反應混合物1h。然後添加(2-甲基-3-側氧基-哌嗪-2-基)-乙酸甲酯(2.63g,14.1mmol)並使反應混合物回流2h。濃縮反應混合物並藉由在矽膠上之管柱層析(70% EA/己烷)純化所得粗製物,獲得呈灰白色固體之標題化合物(4.37g,85%),MS:m/e=436.2(M+H+)。 To a solution of 2,6-difluoro-4-iodo-phenylamine (3.00 g, 11.8 mmol) in toluene (80 ml) was added CDI (5.72 g, 35.3 mmol) and the reaction mixture was stirred at 110 ° C for 1 h. (2-methyl-3-oxo-piperazin-2-yl) -methyl acetate (2.63 g, 14.1 mmol) was then added and the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated and the obtained crude product was purified by column chromatography on silica gel (70% EA / hexane) to obtain the title compound (4.37 g, 85%) as an off-white solid, MS: m / e = 436.2 ( M + H + ).
步驟2:(9aRS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮: Step 2: (9aRS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2,3,4,9-tetra Hydropyrazino [1,2-c] pyrimidine-1,6,8-trione:
在氬氣下,向(9aRS)-7-(2,6-二氟-4-碘苯基)-9a-甲基四氫-1H-吡嗪并[1,2-c]嘧啶-1,6,8(2H,7H)-三酮(實例109步驟1)(2.5g,5.74mmol)含於THF(15ml)中之溶液添加1-乙炔基-2-氟苯(1.04g,977μl,8.62mmol)、Et3N(2.91g,4ml,28.7mmol)、雙(三苯基膦)氯化鈀(II)(80.6mg,115μmol,0.02eq.)、三苯基膦(15.1mg,57.4μmol,0.01 eq.)及碘化銅(I)(5.47mg,28.7μmol,0.005eq.)。將該反應混合物加熱至50℃並攪拌2h。藉由急驟層析(矽膠,50g,50%至100% EtOAc/庚烷)純化粗物質。在真空中濃縮溶離份,得到2.00g呈白色粉末之標題化合物,MS:m/e=428.2(M+H+)。 Under argon, (9aRS) -7- (2,6-difluoro-4-iodophenyl) -9a-methyltetrahydro-1H-pyrazino [1,2-c] pyrimidine-1, 6,8 (2H, 7H) -trione (Example 109, step 1) (2.5 g, 5.74 mmol) in THF (15 ml) was added as a solution of 1-ethynyl-2-fluorobenzene (1.04 g, 977 μl, 8.62 mmol), Et 3 N (2.91 g, 4 ml, 28.7 mmol), bis (triphenylphosphine) palladium (II) chloride (80.6 mg, 115 μmol, 0.02 eq.), triphenyl phosphine (15.1 mg, 57.4 μmol , 0.01 eq.) And copper (I) iodide (5.47 mg, 28.7 μmol, 0.005 eq.). The reaction mixture was heated to 50 ° C and stirred for 2 h. The crude material was purified by flash chromatography (silica gel, 50 g, 50% to 100% EtOAc / heptane). The fractions were concentrated in vacuo to give 2.00 g of the title compound as a white powder, MS: m / e = 428.2 (M + H + ).
步驟3:(9aS)-及(9aR)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 3: (9aS)-and (9aR) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2,3, 4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione:
藉由對掌性HPLC,使用Chiral AD管柱,使用(庚烷/EtOH-60/40)實現對映異構體之對掌性分離,得到呈淺黃色固體之(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:428.3(M+H+));及呈淺黃色固體之(9aR)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:428.3(M+H+))。 Enantiomeric separation of enantiomers was achieved by chiral HPLC using a Chiral AD column using (heptane / EtOH-60 / 40) to obtain (9aS) -7- [2 as a pale yellow solid , 6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c] Pyrimidine-1,6,8-trione (MS: 428.3 (M + H + )); and (9aR) -7- [2,6-difluoro-4- [2- (2- (2- Fluorophenyl) ethynyl] phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (MS: 428.3 (M + H + )).
步驟4:(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2-(3-吡啶基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 4: (9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2- (3-pyridyl)- 4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例109步驟3)及3-碘吡啶獲得呈白色固體之標題化合物,MS:m/e=505.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl -2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 109, step 3) and 3-iodopyridine to give the title compound as a white solid, MS: m / e = 505.3 (M + H + ).
實例110Example 110
(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2-嘧啶-4-基-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2-pyrimidin-4-yl-4,9- Dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例1步驟3中所述之化學作用,自(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例109步驟3)及4-溴嘧啶鹽酸鹽獲得呈淺黃色固體之標題化合物,MS:m/e=506.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 3, from (9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a- Methyl-2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 109, step 3) and 4-bromopyrimidine hydrochloride were obtained The title compound as a yellow solid, MS: m / e = 506.2 (M + H + ).
實例111Example 111
(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl-2- (1-methylpyrazole-4- ) -4,9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
使用類似於實例5中所述之化學作用,自(9aS)-7-[2,6-二氟-4-[2-(2-氟苯基)乙炔基]苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例109步驟3)及4-碘-1-甲基-1H-吡唑獲得呈淺黃色結晶固體之標題化合物,MS:m/e=508.3(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2,6-difluoro-4- [2- (2-fluorophenyl) ethynyl] phenyl] -9a-methyl -2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 109, step 3) and 4-iodo-1-methyl-1H-pyridine The azole gave the title compound as a pale yellow crystalline solid, MS: m / e = 508.3 (M + H + ).
實例112Example 112
(9aS)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮(9aS) -7- [2-Chloro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-4-yl) -4,9-di Hydrogen-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione
步驟1:2-氯-4-苯基乙炔基-苯基胺Step 1: 2-Chloro-4-phenylethynyl-phenylamine
使用類似於實例1步驟1中所述之化學作用,自2-氯-4-碘苯胺及苯基乙炔獲得呈淺棕色固體之標題化合物,MS:m/e=228.1,230.0(M+H+)。 The title compound was obtained as a light brown solid from 2-chloro-4-iodoaniline and phenylacetylene using a chemical reaction similar to that described in Step 1 of Example 1, MS: m / e = 228.1, 230.0 (M + H + ).
步驟2:(9aRS)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-Step 2: (9aRS) -7- [2-Chloro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9- 四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例1步驟2中所述之化學作用,自2-氯-4-苯基乙炔基-苯基胺(實例112步驟1)及2-[(2RS)-2-甲基-3-側氧基-哌嗪-2-基]乙酸甲酯獲得呈白色固體之標題化合物,MS:m/e=406.3,408.2(M+H+)。 Using a chemical reaction similar to that described in Example 1, Step 2 from 2-chloro-4-phenylethynyl-phenylamine (Example 112, Step 1) and 2-[(2RS) -2-methyl-3- The pendant oxy-piperazin-2-yl] acetate gave the title compound as a white solid, MS: m / e = 406.3, 408.2 (M + H + ).
步驟3:(9aS)-及(9aR)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 3: (9aS)-and (9aR) -7- [2-chloro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazine And [1,2-c] pyrimidine-1,6,8-trione:
藉由對掌性HPLC,使用Reprosil Chiral NR管柱,使用(庚烷/EtOH-60/40)實現對映異構體之對掌性分離,得到呈白色固體之(9aS)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:428.3(M+H+));及呈白色固體之(9aR)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(MS:428.3(M+H+))。 Reversal HPLC, using a Reprosil Chiral NR column, and using (heptane / EtOH-60 / 40) to achieve the enantiomeric separation of the enantiomers gave (9aS) -7- [2 as a white solid -Chloro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8- Triketone (MS: 428.3 (M + H + )); and (9aR) -7- [2-chloro-4- (2-phenylethynyl) phenyl] -9a-methyl-2 as a white solid , 3,4,9-tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (MS: 428.3 (M + H + )).
步驟4:(9aS)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2-(1-甲基吡唑-4-基)-4,9-二氫-3H-吡嗪并[1,2-c]嘧啶-1,6,8-三酮:Step 4: (9aS) -7- [2-Chloro-4- (2-phenylethynyl) phenyl] -9a-methyl-2- (1-methylpyrazol-4-yl) -4, 9-dihydro-3H-pyrazino [1,2-c] pyrimidine-1,6,8-trione:
使用類似於實例5中所述之化學作用,自(9aS)-7-[2-氯-4-(2-苯基乙炔基)苯基]-9a-甲基-2,3,4,9-四氫吡嗪并[1,2-c]嘧啶-1,6,8-三酮(實例112步驟3)及4-碘-1-甲基-1H-吡唑獲得呈灰白色固體之標題化合物,MS:m/e=488.2,490.2(M+H+)。 Using a chemical action similar to that described in Example 5, from (9aS) -7- [2-chloro-4- (2-phenylethynyl) phenyl] -9a-methyl-2,3,4,9 -Tetrahydropyrazino [1,2-c] pyrimidine-1,6,8-trione (Example 112, step 3) and 4-iodo-1-methyl-1H-pyrazole to give the title compound as an off-white solid , MS: m / e = 488.2, 490.2 (M + H + ).
圖1:說明mGlu4 PAM Ca2+動員篩選分析之實驗結果及EC50及% Emax值之測定。 Figure 1: Illustrates the experimental results of mGlu4 PAM Ca 2+ mobilization screening analysis and the determination of EC 50 and% E max values.
Claims (12)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15179550 | 2015-08-03 | ||
??15179550.7 | 2015-08-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201718589A TW201718589A (en) | 2017-06-01 |
TWI621619B true TWI621619B (en) | 2018-04-21 |
Family
ID=53776452
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW105124484A TWI621619B (en) | 2015-08-03 | 2016-08-02 | Ethynyl derivatives |
Country Status (21)
Country | Link |
---|---|
US (1) | US10011607B2 (en) |
EP (1) | EP3331882B1 (en) |
JP (1) | JP6975511B2 (en) |
KR (1) | KR20180030857A (en) |
CN (1) | CN107667107B (en) |
AR (1) | AR105556A1 (en) |
AU (1) | AU2016302696B2 (en) |
BR (1) | BR112017023951A2 (en) |
CA (1) | CA2983908A1 (en) |
CL (1) | CL2018000278A1 (en) |
CO (1) | CO2017011010A2 (en) |
HK (1) | HK1246790A1 (en) |
IL (1) | IL255103B (en) |
MX (1) | MX2018001486A (en) |
PE (1) | PE20180357A1 (en) |
PH (1) | PH12018500247A1 (en) |
RU (1) | RU2722014C9 (en) |
TW (1) | TWI621619B (en) |
UA (1) | UA120888C2 (en) |
WO (1) | WO2017021384A1 (en) |
ZA (1) | ZA201707015B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL3331863T3 (en) | 2015-08-03 | 2020-08-10 | Glenmark Pharmaceuticals S.A. | Novel compounds as ror gamma modulators |
CA2994717A1 (en) | 2015-08-03 | 2017-02-09 | Bristol-Myers Squibb Company | Heterocyclic compounds useful as modulators of tnf alpha |
GB201513742D0 (en) | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonists |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015044075A1 (en) * | 2013-09-25 | 2015-04-02 | F. Hoffmann-La Roche Ag | Ethynyl derivatives |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103079570A (en) * | 2009-11-06 | 2013-05-01 | 范德比尔特大学 | Aryl and heteroaryl sulfones as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction |
US8420661B2 (en) * | 2010-04-13 | 2013-04-16 | Hoffmann-La Roche Inc. | Arylethynyl derivatives |
SG194095A1 (en) * | 2011-04-26 | 2013-11-29 | Hoffmann La Roche | Pyrazolidin-3-one derivatives |
TWI649310B (en) * | 2014-01-10 | 2019-02-01 | 赫孚孟拉羅股份公司 | Acetylene derivative |
EA029261B1 (en) * | 2014-02-25 | 2018-02-28 | Ф. Хоффманн-Ля Рош Аг | Ethynyl derivatives |
-
2016
- 2016-08-01 AR ARP160102335A patent/AR105556A1/en unknown
- 2016-08-02 RU RU2018105872A patent/RU2722014C9/en active
- 2016-08-02 JP JP2018505431A patent/JP6975511B2/en active Active
- 2016-08-02 CA CA2983908A patent/CA2983908A1/en not_active Abandoned
- 2016-08-02 TW TW105124484A patent/TWI621619B/en not_active IP Right Cessation
- 2016-08-02 WO PCT/EP2016/068359 patent/WO2017021384A1/en active Application Filing
- 2016-08-02 UA UAA201801410A patent/UA120888C2/en unknown
- 2016-08-02 AU AU2016302696A patent/AU2016302696B2/en not_active Ceased
- 2016-08-02 EP EP16745473.5A patent/EP3331882B1/en active Active
- 2016-08-02 KR KR1020187003005A patent/KR20180030857A/en not_active Application Discontinuation
- 2016-08-02 BR BR112017023951-5A patent/BR112017023951A2/en not_active Application Discontinuation
- 2016-08-02 CN CN201680029481.6A patent/CN107667107B/en active Active
- 2016-08-02 PE PE2017002405A patent/PE20180357A1/en unknown
- 2016-08-02 MX MX2018001486A patent/MX2018001486A/en active IP Right Grant
-
2017
- 2017-10-17 ZA ZA2017/07015A patent/ZA201707015B/en unknown
- 2017-10-18 IL IL255103A patent/IL255103B/en active IP Right Grant
- 2017-10-27 CO CONC2017/0011010A patent/CO2017011010A2/en unknown
-
2018
- 2018-01-10 US US15/867,097 patent/US10011607B2/en active Active
- 2018-01-31 CL CL2018000278A patent/CL2018000278A1/en unknown
- 2018-02-01 PH PH12018500247A patent/PH12018500247A1/en unknown
- 2018-05-16 HK HK18106336.0A patent/HK1246790A1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015044075A1 (en) * | 2013-09-25 | 2015-04-02 | F. Hoffmann-La Roche Ag | Ethynyl derivatives |
Also Published As
Publication number | Publication date |
---|---|
RU2018105872A3 (en) | 2019-12-26 |
IL255103B (en) | 2020-01-30 |
CA2983908A1 (en) | 2017-02-09 |
MX2018001486A (en) | 2018-03-15 |
AR105556A1 (en) | 2017-10-18 |
CN107667107A (en) | 2018-02-06 |
JP6975511B2 (en) | 2021-12-01 |
RU2018105872A (en) | 2019-09-05 |
BR112017023951A2 (en) | 2018-07-24 |
RU2722014C2 (en) | 2020-05-26 |
CO2017011010A2 (en) | 2018-02-09 |
IL255103A0 (en) | 2017-12-31 |
CN107667107B (en) | 2021-05-18 |
PH12018500247A1 (en) | 2018-08-13 |
ZA201707015B (en) | 2018-11-28 |
CL2018000278A1 (en) | 2018-07-06 |
TW201718589A (en) | 2017-06-01 |
US20180127429A1 (en) | 2018-05-10 |
UA120888C2 (en) | 2020-02-25 |
HK1246790A1 (en) | 2018-09-14 |
EP3331882B1 (en) | 2020-04-29 |
JP2018522037A (en) | 2018-08-09 |
AU2016302696B2 (en) | 2020-05-07 |
PE20180357A1 (en) | 2018-02-21 |
KR20180030857A (en) | 2018-03-26 |
EP3331882A1 (en) | 2018-06-13 |
AU2016302696A1 (en) | 2017-11-02 |
RU2722014C9 (en) | 2020-10-22 |
WO2017021384A1 (en) | 2017-02-09 |
US10011607B2 (en) | 2018-07-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10696658B2 (en) | Heteroaromatic compounds and their use as dopamine D1 ligands | |
AU2011251321B2 (en) | Nitrogen-containing heterocyclic compound having kynurenine production inhibitory activity | |
EP3889134A1 (en) | Compound for inhibiting pge2/ep4 signaling transduction inhibiting, preparation method therefor, and medical uses thereof | |
TWI553011B (en) | Heteroaromatic compounds and their use as dopamine d1 ligands | |
TWI527801B (en) | Ethynyl derivatives | |
TWI621619B (en) | Ethynyl derivatives | |
JP2015508775A5 (en) | ||
US9850232B2 (en) | Heteroaromatic compounds and their use as dopamine D1 ligands | |
CN107207481B (en) | 3- (4-ethynylphenyl) hexahydropyrimidine-2, 4-dione derivatives as modulators of MGLUR4 | |
EP3134405B1 (en) | Heteroaromatic compounds and their use as dopamine d1 ligands |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |